WO2006017171A2 - Methods of diagnosing & treating obesity, diabetes and insulin resistance - Google Patents

Abstract

The present invention provides compositions and methods for diagnosing and treating obesity, diabetes and insulin resistance. In particular, the invention provides methods of identifying modulators of the polynucleotides or polypeptides of the invention and using those modulators to treat obesity and/or diabetes, as well as methods of diagnosing obesity and/or diabetes by measuring the levels of the polynucleotides or polypeptides of the invention in a patient.

Description

Methods of Diagnosing & Treating Obesity, Diabetes and Insulin

Resistance

CROSS-REFERENCE TO RELATED APPLICATIONS [01] This application claims benefit of U.S. Provisional Application No.

60/587,780, filed July 13, 2004, which is herein incorporated by reference.

BACKGROUND OF THE INVENTION [02] Obesity has reached epidemic proportions globally with more than 1 billion adults overweight- at least 300 million of them clinical obese- and is a major contributor to the global burden of chronic disease and disability. Overweight and obesity leads to adverse metabolic effect on blood pressure, cholesterol, triglycerides and insulin resistance. The non-fatal but debilitating health problems associated with obesity include respiratory difficulties, chronic musculoskeletal problems, skin problems and infertility. The more life-threatening problems fall into four main areas: cardiovascular disease problems, conditions associated with insulin resistance such as Type 2 diabetes, certain types of cancers especially the hormonally related and large-bowel cancers, and gall bladder disease. The likelihood of developing Type 2 diabetes and hypertension rises steeply with increasing body fatness. Weight reduction leads to correction of a number of obesity- associated endocrine and metabolic disorders.

[03] Effective weight management for individuals and groups at risk of developing obesity involves a range of long term strategies. These include prevention, weight maintenance, management of co-morbidities and weight loss. Existing treatment strategies include calorific restriction programs, surgery (gastric stapling) and drug intervention. The currently available anti-obesity drugs can be divided into two classes: central acting and peripheral acting. Three marketed drugs are Xenical (Orlistat), Merida (Sibutramine) and Adipex-P (Phentermine). Xenical is a non-systemic acting GI lipase inhibitor which is indicated for short and long term obesity management. Merida reduces food intake by re¬ uptake inhibition of primarily norepinephrine and serotonin. Adipex-P is a phenteramine with sympathomimetic activities and suppresses appetite. It is indicated only for short term use. A more drastic solution to permanent weight loss is surgery and a gastric by-pass which limits absorption of calories through massive reduction in stomach size. [04] Carrying extra body weight and body fat go hand and hand with the development of diabetes. People who are overweight (BMI greater than 25) are at a much greater risk of developing type 2 diabetes than normal weight individuals. Almost 90% of people with type 2 diabetes are overweight. [05] Diabetes mellitus can be divided into two clinical syndromes, Type 1 and Type 2 diabetes mellitus. Type 1, or insulin-dependent diabetes mellitus (IDDM), is a chronic autoimmune disease characterized by the extensive loss of beta cells in the pancreatic Islets of Langerhans, which produce insulin. As these cells are progressively destroyed, the amount of secreted insulin decreases, eventually leading to hyperglycemia (abnormally high level of glucose in the blood) when the amount of secreted insulin drops below the level required for euglycemia (normal blood glucose level). Although the exact trigger for this immune response is not known, patients with IDDM have high levels of antibodies against proteins expressed in pancreatic beta cells. However, not all patients with high levels of these antibodies develop IDDM. [06] Type 2 diabetes (also referred to as non-insulin dependent diabetes mellitus (NIDDM)) develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond (called insulin resistance) may be due to reduced numbers of insulin receptors on these cells, or a dysfunction of signaling pathways within the cells, or both. The beta cells initially compensate for this insulin resistance by increasing insulin output. Over time, these cells become unable to produce enough insulin to maintain normal glucose levels, indicating progression to Type 2 diabetes.

[07] Type 2 diabetes is brought on by a combination of genetic and acquired risk factors - including a high-fat diet, lack of exercise, and aging. Worldwide, Type 2 diabetes has become an epidemic, driven by increases in obesity and a sedentary lifestyle, widespread adoption of western dietary habits, and the general aging of the population in many countries. In 1985, an estimated 30 million people worldwide had diabetes ~ by 2000, this figure had increased 5-fold, to an estimated 154 million people. The number of people with diabetes is expected to double between now and 2025, to about 300 million. [08] Type 2 diabetes is a complex disease characterized by defects in glucose and lipid metabolism. Typically there are perturbations in many metabolic parameters including increases in fasting plasma glucose levels, free fatty acid levels and triglyceride levels, as well as a decrease in the ratio of HDL/LDL. As discussed above, one of the principal underlying causes of diabetes is thought to be an increase in insulin resistance in peripheral tissues, principally muscle and fat.

[09] Therapies aimed at reducing peripheral insulin resistance are available. The most relevant to this invention are drugs of the thiazolidinedione (TZD) class namely troglitazone, pioglitazone, and rosiglitazone. In the US these have been marketed under the names Rezulin™, Avandia™ and Actos™, respectively. The principal effect of these drugs is to improve glucose homeostasis. Notably in diabetics treated with TZDs there are increases in peripheral glucose disposal rates indicative of increased insulin sensitivity in both muscle and fat. [10] The molecular target of TZDs is a member of the PPAR family of ligand-activated transcription factors called PPAR gamma. This transcription factor is highly expressed in adipose tissue with much lower levels being observed in muscle. Binding of TZDs to PPAR gamma in target cells and tissues such as fat and muscle brings about a change in gene expression. The link between TZD-altered gene expression in fat and muscle and increased insulin sensitivity is unknown. The present invention addresses this and other problems.

BRIEF SUMMARY OF THE INVENTION [11] The present invention provides methods for identifying an agent for treating an obese, diabetic or pre-diabetic individual. In some embodiments, the method comprises the steps of: (i) contacting an agent to a polypeptide encoded by a polynucleotide that is substantially identical to or hybridizes to a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C, wherein the polypeptide optionally has the activity listed in Table 1; and (ii) selecting an agent that modulates the expression or activity of the polypeptide or that binds to the polypeptide, thereby identifying an agent for treating an obese, diabetic or pre-diabetic individual. Table 1: List of Polypeptides, SEQ ID numbers and Proposed Activity

[12] In some embodiments, the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or a protein domain thereof. In some embodiments, the method further comprises detecting whether the selected agent modulates weight and/or obesity. In some embodiments, the method further comprises detecting whether the selected agent modulates insulin sensitivity. [13] In some embodiments, step (ii) comprises selecting an agent that modulates expression of the polypeptide. In some embodiments, step (ii) comprises selecting an agent that modulates the activity of the polypeptide. In some embodiments, step (ii) comprises selecting an agent that specifically binds to the polypeptide.

[14] In some embodiments, the polypeptide is expressed in a cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129.

[15] The present invention also provides methods of reducing body weight in an animal. In some embodiments, the methods comprise administering to the animal an effective amount of an agent that modulates the activity or expression of cell and the cell is contacted with the agent, hi some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129. [16] In some embodiments, the agent is selected by a method comprising (i) contacting an agent to a mixture comprising a polypeptide encoded by a polynucleotide substantially identical to, or that hybridizes to, a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C, wherein the polypeptide optionally has the activity listed in Table 1 ; and (ii) selecting an agent that modulates the expression or activity of the polypeptide or that binds to the polypeptide.

[17] In some embodiments, the agent is an antibody. In some embodiments, the antibody is a monoclonal antibody, hi some embodiments, the animal is a human.

[18] The present invention also provides methods of treating a diabetic or pre-diabetic animal. In some embodiments, the method comprising administering to the animal a therapeutically effective amount of an agent that modulates the activity or expression of cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129. In some embodiments, the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or a protein domain thereof.

[19] hi some embodiments, the agent is selected by a method comprising (i) contacting an agent to a mixture comprising a polypeptide encoded by a polynucleotide that hybridizes to a nucleic acid encoding cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129 in 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C; and (ii) selecting an agent that modulates the expression or activity of the polypeptide or that binds to the polypeptide.

[20] In some embodiments, the agent is an antibody. In some embodiments, the antibody is a monoclonal antibody, hi some embodiments, the animal is a human. [21] The present invention also provides methods of introducing an expression cassette into a cell. In some embodiments, the methods comprise introducing into the cell an expression cassette comprising a promoter operably linked to a polynucleotide encoding a polypeptide, wherein the polynucleotide is substantially identical to or hybridizes to a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C, and the polypeptide optionally has the activity listed in Table 1. hi some embodiments, the polypeptide comprises an amino acid sequence at least 95% identical to

SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or a protein domain thereof. [22] hi some embodiments, the polypeptide is expressed in a cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129. In some embodiments, the cell is selected from the group consisting of an adipocyte and a skeletal muscle cell.

[23] hi some embodiments, the method further comprises introducing the cell into a human. In some embodiments, the human is obese, hi some embodiments, the human is diabetic. In some embodiments, the human is prediabetic. In some embodiments, the cell is from the human.

[24] The present invention also provides methods of diagnosing an individual who has obesity, Type 2 diabetes or has a predisposition for diabetes or obesity, hi some embodiments, the method comprises detecting in a sample from the individual the level of a polypeptide or the level of a polynucleotide encoding the polypeptide, wherein the polynucleotide is substantially identical to or hybridizes to a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C, wherein a modulated level of the polypeptide or polynucleotide in the sample compared to a level of the polypeptide or polynucleotide in either a lean individual or a previous sample from the individual indicates that the individual is obese or diabetic or has a predisposition for diabetes or obesity.

[25] hi some embodiments, the detecting step comprises contacting the sample with an antibody that specifically binds to the polypeptide. In some embodiments, the amino acid sequence is expressed in a cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129. In some embodiments, the detecting step comprises quantifying mRNA encoding the polypeptide. In some embodiments, the mRNA is reverse transcribed and amplified in a polymerase chain reaction. In some embodiments, the sample is a blood, urine or tissue sample.

[26] The present invention provides for an isolated nucleic acid that is substantially identical to or hybridizes to a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C. hi some embodiments, the polynucleotide comprises SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126 or 128. [27] In some embodiments, the polynucleotide is encoded by a cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129. [28] The present invention also provides expression cassettes comprising a heterologous promoter operably linked to a nucleic acid that is substantially identical to or hybridizes to a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C. [29] The present invention also provides host cells transfected with nucleic acids that is substantially identical to or hybridizes to a nucleic acid encoding a polypeptide listed in Table 1 under hybridization conditions of 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1% SDS at 55⁰C. In some embodiments, the host cell is a human cell. In some embodiments, the host cell is a bacterium.

[30] The present invention also provides isolated polypeptides comprising an amino acid sequence at least 70% identical to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or fragments thereof. In some embodiments, the polypeptide is encoded by a cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129.

[31] The present invention also provides antibodies that specifically bind to a polypeptide selected from the groups consisting of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129.

[32] The present invention also provides pharmaceutical compositions comprising polypeptides comprising an amino acid sequence at least 70% identical to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or fragments thereof, and a pharmaceutically-acceptable excipient.

DEFINITIONS

[33] "Insulin sensitivity" refers to the ability of a cell or tissue to respond to insulin. Responses include, e.g., glucose uptake of a cell or tissue in response to insulin stimulation. Sensitivity can be determined at an organismal, tissue or cellular level. For example, blood or urine glucose levels following a glucose tolerance test are indicative of insulin sensitivity. Other methods of measuring insulin sensitivity include, e.g., measuring glucose uptake (see, e.g., Garcia de Herreros, A., and Birnbaum, M. J. J. Biol. Chem. 264, 19994-19999 (1989); Klip, A., Li, G., and Logan, WJ. Am. J. Physiol. 247, E291-296 (1984)), measuring the glucose infusion rate (GINF) into tissue such as the skeletal muscle (see, e.g., Ludvik et al., J. Clin. Invest. 100:2354 (1997); Frias et al, Diabetes Care 23:64, (2000)) and measuring sensitivity of GLUT4 translocation (e.g., as described herein) in response to insulin.

[34] As used herein, an overweight person has a body mass index (BMI) > 25 and an "obese" person has a BMI ≥ 30. BMI is calculated as the weight in kilograms divided by the square of the height in meters.

[35] The term "waist-to-hip ratio or WHR" is the ratio of a person's waist circumference to hip circumference, . For most people, carrying extra weight around their middle increases health risks more than carrying extra weight around their hips or thighs. For both men and women, a waist-to-hip ratio of 1.0 or higher is considered "at risk" or in the danger zone for undesirable health consequences, such as heart disease and other ailments connected with being overweight. [36] The term "adipogenic," when used in reference to cells refers to a cell which can become an adipocyte. An "adipogenic factor" refers to a factor (including, e.g., a protein (or glycoprotein)) that can induce or stimulate the differentiation of cells into an adipocyte. Exemplary adipogenic factors include, e.g., _Wntl0b, Pref-l,ADF and TNF-alpha. [37] The term "lipid metabolism" refers to the in vivo process of catabolism (decomposition) and anabolism (accumulation) of lipids (e.g., triglycerides derived from food) and is intended to include, in the broad sense, reactions for transforming lipids into energy, biosynthesis of fatty acids, acylglycerol, phospholipid metabolism and cholesterol metabolism.

[38] "Activity" of a polypeptide of the invention refers to structural, regulatory, or biochemical functions of a polypeptide in its native cell or tissue. Examples of activity of a polypeptide include both direct activities and indirect activities. Exemplary direct activities are the result of direct interaction with the polypeptide, , e.g., enzymatic activity, ligand binding, production or depletion of second messengers (e.g., cAMP, cGMP, IP₃, DAG, or Ca²⁺), ion flux, phosphorylation levels, transcription levels, and the like. Exemplary indirect activities are observed as a change in phenotype or response in a cell or tissue to a polypeptide's directed activity, e.g., loss of body weight or molecular events associated with loss of body weight or obesity or modulating insulin sensitivity of a cell as a result of the interaction of the polypeptide with other cellular or tissue components. [39] . "Predisposition for diabetes" occurs in a person when the person is at high risk for developing diabetes. A number of risk factors are known to those of skill in the art and include: genetic factors (e.g., carrying alleles that result in a higher occurrence of diabetes than in the average population or having parents or siblings with diabetes); overweight (e.g., body mass index (BMI) greater or equal to 25 kg/m²); habitual physical inactivity, race/ethnicity (e.g., African- American, Hispanic- American, Native Americans, Asian- Americans, Pacific Islanders); previously identified impaired fasting glucose or impaired glucose tolerance, hypertension (e.g., greater or equal to 140/90 mmHg in adults); HDL cholesterol less than or equal to 35 mg/dl; triglyceride levels greater or equal to 250 mg/dl; a history of gestational diabetes or delivery of a baby over nine pounds; and/or polycystic ovary syndrome. See, e.g., "Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus" and "Screening for Diabetes" Diabetes Care 25(1): S5- S24 (2002).

[40] A "lean individual," when used to compare with a sample from a patient, refers to an adult with a fasting blood glucose level less than 100 mg/dl or a 2 hour PG reading of 140 mg/dl. "Fasting" refers to no caloric intake for at least 8 hours. A "2 hour PG" refers to the level of blood glucose after challenging a patient to a glucose load containing the equivalent of 75g anhydrous glucose dissolved in water. The overall test is generally referred to as an oral glucose tolerance test (OGTT). See, e.g., Diabetes Care, 2003, 26(11 ) : 3160-3167 (2003). The level of a polypeptide in a lean individual can be a reading from a single individual, but is typically a statistically relevant average from a group of lean individuals. The level of a polypeptide in a lean individual can be represented by a value, for example in a computer program.

[41] A "pre-diabetic individual," when used to compare with a sample from a patient, refers to an adult with a fasting blood glucose level greater than 100 mg/dl but less than 126 mg/dl or a 2 hour PG reading of greater than 140 mg/dl but less than 200mg/dl. A "diabetic individual," when used to compare with a sample from a patient, refers to an adult with a fasting blood glucose level greater than 126 mg/dl or a 2 hour PG reading of greater than 200 mg/dl. [42] An "agonist" refers to an agent that binds to, stimulates, increases, activates, facilitates, enhances activation, sensitizes or up regulates the activity or expression of a polypeptide of the invention. [43] An "antagonist" refers to an agent that binds to, partially or totally blocks stimulation, decreases, prevents, delays activation, inactivates, desensitizes, or down regulates the activity or expression of a polypeptide of the invention.

[44] "Antibody" refers to a polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof which specifically bind and recognize an analyte (antigen). The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.

[45] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (V_L) and variable heavy chain (VH) refer to these light and heavy chains respectively.

[46] Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'_2; a dimer of Fab which itself is a light chain joined to V_H-C_HI by a disulfide bond. The F(ab)'₂ may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'₂ dimer into an Fab' monomer. The Fab' monomer is essentially an Fab with part of the hinge region (see, Paul (Ed.) Fundamental Immunology, Third Edition, Raven Press, NY (1993)). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv). [47] The terms "peptidomimetic" and "mimetic" refer to a synthetic chemical compound that has substantially the same structural and functional characteristics of the antagonists or agonists of the invention. Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics" (Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger 2BVS p. 392 (1985); and Evans et al. J. Med. Chan. 30:1229 (1987), which are incorporated herein by reference). Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent or enhanced therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a biological or pharmacological activity), such as a polypeptide exemplified in this application, but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of, e.g., -CH2NH-, -CH2S-, -CH2-CH2-, - CH=CH- (cis and trans), -COCH2-, -CH(OH)CH2-, and -CH2SO-. The mimetic can be either entirely composed of synthetic, non-natural analogues of amino acids, or, is a chimeric molecule of partly natural peptide amino acids and partly non-natural analogs of amino acids. The mimetic can also incorporate any amount of natural amino acid conservative substitutions as long as such substitutions also do not substantially alter the mimetic' s structure and/or activity. For example, a mimetic composition is within the scope of the invention if it is capable of carrying out the binding or other activities of an agonist or antagonist of a polypeptide of the invention.

[48] The term "gene" means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons).

[49] The term "isolated," when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It is preferably in a homogeneous state although it can be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. In particular, an isolated gene is separated from open reading frames that flank the gene and encode a protein other than the gene of interest. The term "purified" denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[50] The term "nucleic acid" or "polynucleotide" refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double- stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzcr et at., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et ah, J. Biol. Chem. 260:2605-2608 (1985); and Cassol et al. (1992); Rossolini et al.,Mol. Cell. Probes 8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, and mRNA encoded by a gene.

[51] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. As used herein, the terms encompass amino acid chains of any length, including full-length proteins (i.e., antigens), wherein the amino acid residues are linked by covalent peptide bonds.

[52] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ -carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. "Amino acid mimetics" refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but which functions in a manner similar to a naturally occurring amino acid.

[53] Amino acids may be referred to herein by either the commonly known three letter symbols or by the one-letter symbols recommended by the IUP AC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[54] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein that encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid that encodes a polypeptide is implicit in each described sequence.

[55] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.

[56] The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E);

3) Asparagine (N), Glutamine (Q);

4) Arginine (R), Lysine (K);

5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);

6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and

8) Cysteine (C), Methionine (M) {see, e.g., Creighton, Proteins (1984)).

[57] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions {i.e., gaps) as compared to the reference sequence (e.g., a polypeptide of the invention), which does not comprise additions or deletions, for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[58] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same sequences. Sequences are "substantially identical" if two sequences have a specified percentage of amino acid residues or nucleotides that are the same {i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection, or across the entire sequence where not indicated. The invention provides polypeptides or polynucleotides that are substantially identical to the polypeptides or polynucleotides, respectively, exemplified herein (e.g., SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 61, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128 or 129).

[59] This definition also refers to the complement of a test sequence. Optionally, the identity exists over a region that is at least about 50 nucleotides in length, or more preferably over a region that is 100 to 500 or 1000 or more nucleotides in length. [60] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[61] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. MoI. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat 'I. Acad. ScL USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[62] Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. MoI. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive- valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al, supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative- scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. ScL USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=M-, and a comparison of both strands.

[63] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g. , Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[64] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[65] The phrase "selectively (or specifically) hybridizes to" refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence under stringent hybridization conditions when that sequence is present in a complex mixture (e.g., total cellular or library DNA or RNA).

[66] The phrase "stringent hybridization conditions" refers to conditions under which a probe will hybridize to its target subsequence, typically in a complex mixture of nucleic acid, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology— Hybridization with Nucleic Probes, "Overview of principles of hybridization and the strategy of nucleic acid assays" (1993). Generally, stringent conditions are selected to be about 5-10° C lower than the thermal melting point (T_m) for the specific sequence at a defined ionic strength pH. The T_m is the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at T_m, 50% of the probes are occupied at equilibrium). Stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 3O⁰C for short probes (e.g., 10 to 50 nucleotides) and at least about 60° C for long probes (e.g., greater than 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, optionally 10 times background hybridization. Exemplary stringent hybridization conditions can be as following: 50% formamide, 5X SSC, and 1% SDS, incubating at 42⁰C, or 5X SSC, 1% SDS, incubating at 65⁰C, with wash in 0.2X SSC, and 0.1% SDS at 55⁰C, 6O⁰C, or 65⁰C. Such washes can be performed for 5, 15, 30, 60, 120, or more minutes.

[67] Nucleic acids that do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides that they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary "moderately stringent hybridization conditions" include a hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37⁰C, and a wash in IX SSC at 45⁰C. Such washes can be performed for 5, 15, 30, 60, 120, or more minutes. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency. [68] The phrase "a nucleic acid sequence encoding" refers to a nucleic acid which contains sequence information for a structural RNA such as rRNA, a tRNA, or the primary amino acid sequence of a specific protein or peptide, or a binding site for a trans¬ acting regulatory agent. This phrase specifically encompasses degenerate codons (i.e., different codons which encode a single amino acid) of the native sequence or sequences that may be introduced to conform with codon preference in a specific host cell.

[69] The term "recombinant" when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (nonrecombinant) form of the cell or express native genes that are otherwise abnormally expressed, under-expressed or not expressed at all.

[70] The term "heterologous" when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[71] An "expression vector" is a nucleic acid construct, generated recombinantly or synthetically, with a series of specified nucleic acid elements that permit transcription of a particular nucleic acid in a host cell. The expression vector can be part of a plasmid, virus, or nucleic acid fragment. Typically, the expression vector includes a nucleic acid to be transcribed operably linked to a promoter.

[72] The phrase "specifically (or selectively) binds to an antibody" or "specifically (or selectively) immunoreactive with", when referring to a protein or peptide, refers to a binding reaction which is determinative of the presence of the protein in the presence of a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein and do not bind in a significant amount to other proteins present in the sample. Specific binding to an antibody under such conditions may require an antibody that is selected for its specificity for a particular protein. For example, antibodies raised against a protein having an amino acid sequence encoded by any of the polynucleotides of the invention can be selected to obtain antibodies specifically immunoreactive with that protein and not with other proteins, except for polymorphic variants. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays, Western blots, or immunohistochemistry are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, Harlow and Lane Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, NY (1988) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity. Typically, a specific or selective reaction will be at least twice the background signal or noise and more typically more than 10 to 100 times background. [73] "Inhibitors," "activators," and "modulators" of expression or of activity are used to refer to inhibitory, activating, or modulating molecules, respectively, of expression of the polypeptides of the invention as determined using in vitro or in vivo assays to monitor expression or activity. Modulators encompass e.g., ligands, agonists, antagonists, their homologs and mimetics, as well as the polypeptides of the invention, or fragments thereof with antagonist activity or that act to increase overall polypeptide activity (i.e., fragments that have at least some of the activity of the full-length protein). In some cases, fragments of the polypeptides of the invention are at least 20, 50, 75 or 100 amino acids in length. The term "modulator" includes inhibitors and activators. Inhibitors are agents that, e.g., inhibit expression of a polypeptide of the invention or bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of a polypeptide of the invention, e.g., antagonists. Activators are agents that, e.g., induce or activate the expression of a polypeptide of the invention or bind to, stimulate, increase, open, activate, facilitate, or enhance activation, sensitize or up regulate the activity of a polypeptide of the invention, e.g., agonists. Modulators include naturally occurring and synthetic ligands, antagonists, agonists, small chemical molecules and the like. Such assays for inhibitors and activators include, e.g., applying putative modulator compounds to cells expressing a polypeptide of the invention and then determining the functional effects on a polypeptide of the invention activity, as described above. Samples or assays comprising a polypeptide of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition of a polypeptide of the invention is achieved when the polypeptide activity value relative to the control is about 80%, optionally 50% or 25, 10%, 5% or 1%. Activation of the polypeptide is achieved when the polypeptide activity value relative to the control is 110%, optionally 150%, optionally 200, 300%, 400%, 500%, or 1000-3000% or more higher.

DETAILED DESCRIPTION OF THE INVENTION I. INTRODUCTION

[74] The present application demonstrates that, surprisingly, modulated levels of mRNA comprising sequences of the invention occur in human adipose tissue collected from either insulin resistant obese non-diabetics or from type 2 diabetic individuals compared to levels of the mRNA in the lean, non-diabetic individuals. Insulin resistant obese individuals are generally predisposed to become type II diabetics. Therefore, the modulation of the sequences in the study described herein indicates the sequences' involvement in obesity, diabetes and/or pre-diabetes.

[75] Without intending to limit the invention to a particular mechanism of action, it is believed that modulation of the expression or activity of the polypeptides or polynucleotides of the invention is beneficial in treating obesity, diabetic, pre-diabetic or insulin resistant, non-diabetic patients. Furthermore, modulated levels of the polypeptides of the invention are indicative of insulin resistance, obesity, diabetes or a predisposition for obesity and/or diabetes. Thus, the detection of a polypeptide of the invention is useful for diagnosis of obesity, predisposition for obesity and/or diabetes, diabetes and/or insulin resistance.

[76] This invention also provides methods of using polypeptides of the invention and modulators of the polypeptides of the invention to diagnose and treat obesity, diabetes, pre-diabetes (including insulin resistant individuals) and related metabolic diseases. The present method also provides methods of identifying modulators of expression or activity of the polypeptides of the invention. Such modulators are useful for treating obesity and/or Type 2 diabetes as well as the pathological aspects of obesity (e.g., increased risk for cardiovascular disease, hypertension or cancer) and/or diabetes (e.g., insulin resistance). II. GENERAL RECOMBINANT NUCLEIC ACID METHODS FOR USE WITH THE INVENTION

[77] In numerous embodiments of the present invention, nucleic acids encoding a polypeptide of the present invention will be isolated and cloned using recombinant methods. Such embodiments are used, e.g., to isolate polynucleotides identical or substantially identical to SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126 or 128 for protein expression or during the generation of variants, derivatives, expression cassettes, or other sequences derived from an polypeptide or polynucleotide of the invention, to monitor gene expression, for the isolation or detection of sequences in different species, for diagnostic purposes in a patient, e.g., to detect mutations in a polypeptide or polynucleotide of the invention or to detect expression levels of nucleic acids or polypeptides. In some embodiments, the sequences encoding the polypeptides of the invention (or polypeptides comprising fragments of the polypeptides of the invention) are operably linked to a heterologous promoter. In some cases, fragments of the polypeptides of the invention are at least 20, 50, 75 or 100 amino acids in length. The polypeptides of the invention can be linked to heterologous amino acid sequences using recombinant DNA technology. In one embodiment, the nucleic acids of the invention are from any mammal, including, in particular, e.g., a human, a mouse, a rat, etc.

[78] Polynucleotides, including expression cassettes, encoding polypeptides of the invention can be introduced into cells and optionally expressed in the cells. Polynucleotides of the invention can be introduced into eukaryotic or prokaryotic cells, including adipocyte or muscle cells. The cells can be primary cells or cell lines. A. General Recombinant Nucleic Acid Methods

[79] This invention relies on routine techniques in the field of recombinant genetics. Basic texts disclosing the general methods of use in this invention include Sambrook et ah, Molecular Cloning, A Laboratory Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expression: A Laboratory Manual (1990); and Current Protocols in Molecular Biology (Ausubel et al, eds., 1994)).

[80] For nucleic acids, sizes are given in either kilobases (kb) or base pairs (bp). These are estimates derived from agarose or acrylamide gel electrophoresis, from sequenced nucleic acids, or from published DNA sequences. For proteins, sizes are given in kilodaltons (kDa) or amino acid residue numbers. Proteins sizes are estimated from gel electrophoresis, from sequenced proteins, from derived amino acid sequences, or from published protein sequences.

[81] Oligonucleotides that are not commercially available can be chemically synthesized according to the solid phase phosphoramidite triester method first described by Beaucage & Caruthers, Tetrahedron Letts. 22:1859-1862 (1981), using an automated synthesizer, as described in Van Devanter et. al, Nucleic Acids Res. 12:6159-6168 (1984). Purification of oligonucleotides is by either native acrylamide gel electrophoresis or by anion-exchange HPLC as described in Pearson & Reanier, J. Chrom. 255:137-149 (1983).

[82] The sequence of the cloned genes and synthetic oligonucleotides can be verified after cloning using, e.g., the chain termination method for sequencing double- stranded templates of Wallace et al, Gene 16:21-26 (1981).

B. Cloning Methods for the Isolation of Nucleotide Sequences Encoding Desired Proteins

[83] In general, the nucleic acids encoding the subject proteins are cloned from DNA sequence libraries that are made to encode cDNA or genomic DNA. The particular sequences can be located by hybridizing with an oligonucleotide probe, the sequence of which can be derived from the sequences disclosed herein, which provide a reference for PCR primers and defines suitable regions for isolating probes specific for the polypeptides or polynucleotides of the invention. Alternatively, where the sequence is cloned into an expression library, the expressed recombinant protein can be detected immunologically with antisera or purified antibodies made against a polypeptide of interest, including those disclosed herein.

[84] Methods for making and screening genomic and cDNA libraries are well known to those of skill in the art {see, e.g., Gubler and Hoffman Gene 25:263-269 (1983); Benton and Davis Science, 196:180-182 (1977); and Sambrook, supra).

[85] Briefly, to make the cDNA library, one should choose a source that is rich in mRNA. The mRNA can then be made into cDNA, ligated into a recombinant vector, and transfected into a recombinant host for propagation, screening and cloning. For a genomic library, the DNA is extracted from a suitable tissue and either mechanically sheared or enzymatically digested to yield fragments of preferably about 5-100 kb. The fragments are then separated by gradient centrifugation from undesired sizes and are constructed in bacteriophage lambda vectors. These vectors and phage are packaged in vitro, and the recombinant phages are analyzed by plaque hybridization. Colony hybridization is carried out as generally described in Grunstein et ah, Proc. Natl. Acad. Sd. USA., 72:3961-3965

(1975).

[86] An alternative method combines the use of synthetic oligonucleotide primers with polymerase extension on an mRNA or DNA template. Suitable primers can be designed from specific sequences disclosed herein. This polymerase chain reaction (PCR) method amplifies the nucleic acids encoding the protein of interest directly from mRNA, cDNA, genomic libraries or cDNA libraries. Restriction endonuclease sites can be incorporated into the primers. Polymerase chain reaction or other in vitro amplification methods may also be useful, for example, to clone nucleic acids encoding specific proteins and express said proteins, to synthesize nucleic acids that will be used as probes for detecting the presence of mRNA encoding a polypeptide of the invention in physiological samples, for nucleic acid sequencing, or for other purposes (see, U.S. Patent Nos. 4,683,195 and

4,683,202). Genes amplified by a PCR reaction can be purified from agarose gels and cloned into an appropriate vector. [87] Appropriate primers and probes for identifying the genes encoding a polypeptide of the invention from mammalian tissues can be derived from the sequences provided herein. For a general overview of PCR, see, Innis et al. PCR Protocols: A Guide to

Methods and Applications, Academic Press, San Diego (1990).

[88] Synthetic oligonucleotides can be used to construct genes. This is done using a series of overlapping oligonucleotides, usually 40-120 bp in length, representing both the sense and anti-sense strands of the gene. These DNA fragments are then annealed, ligated and cloned.

[89] A polynucleotide encoding a polypeptide of the invention can be cloned using intermediate vectors before transformation into mammalian cells for expression. These intermediate vectors are typically prokaryote vectors or shuttle vectors. The proteins can be expressed in either prokaryotes or eukaryotes, using standard methods well known to those of skill in the art.

III. PURIFICATION OF PROTEINS OF THE INVENTION

[90] Either naturally occurring or recombinant polypeptides of the invention can be purified for use in functional assays. Naturally occurring polypeptides of the invention can be purified from any source (e.g., tissues of an organism expressing an ortholog). Recombinant polypeptides can be purified from any suitable expression system. etal

[91] The polypeptides of the invention may be purified to substantial purity by standard techniques, including selective precipitation with such substances as ammonium sulfate; column chromatography, immunopurification methods, and others (see, e.g., Scopes, Protein Purification: Principles and Practice (1982); U.S. Patent No. 4,673,641; Ausubel et ah, supra; and Sambrook et ah, supra).

[92] A number of procedures can be employed when recombinant polypeptides are being purified. For example, proteins having established molecular adhesion properties can be reversibly fused to a polypeptide of the invention. With the appropriate ligand, either protein can be selectively adsorbed to a purification column and then freed from the column in a relatively pure form. The fused protein may be then removed by enzymatic activity. Finally polypeptides can be purified using immunoaffinity columns.

A. Purification of Proteins from Recombinant Bacteria

[93] When recombinant proteins are expressed by the transformed bacteria in large amounts, typically after promoter induction, although expression can be constitutive, the proteins may form insoluble aggregates. There are several protocols that are suitable for purification of protein inclusion bodies. For example, purification of aggregate proteins (hereinafter referred to as inclusion bodies) typically involves the extraction, separation and/or purification of inclusion bodies by disruption of bacterial cells typically, but not limited to, by incubation in a buffer of about 100-150 μg/ml lysozyme and 0.1% Nonidet P40, a non-ionic detergent. The cell suspension can be ground using a Polytron grinder (Brinkman Instruments, Westbury, NY). Alternatively, the cells can be sonicated on ice. Alternate methods of lysing bacteria are described in Ausubel and Sambrook et ah, both supra, and will be apparent to those of skill in the art.

[94] The cell suspension is generally centrifuged and the pellet containing the inclusion bodies resuspended in buffer which does not dissolve but washes the inclusion bodies, e.g., 20 mM Tris-HCl (pH 7.2), 1 mM EDTA, 150 mM NaCl and 2% Triton-X 100, a non-ionic detergent. It may be necessary to repeat the wash step to remove as much cellular debris as possible. The remaining pellet of inclusion bodies may be resuspended in an appropriate buffer (e.g., 20 mM sodium phosphate, pH 6.8, 150 mM NaCl). Other appropriate buffers will be apparent to those of skill in the art.

[95] Following the washing step, the inclusion bodies are solubilized by the addition of a solvent that is both a strong hydrogen acceptor and a strong hydrogen donor (or a combination of solvents each having one of these properties). The proteins that formed the inclusion bodies may then be renatured by dilution or dialysis with a compatible buffer. Suitable solvents include, but are not limited to, urea (from about 4 M to about 8 M), formamide (at least about 80%, volume/volume basis), and guanidine hydrochloride (from about 4 M to about 8 M). Some solvents that are capable of solubilizing aggregate-forming proteins, such as SDS (sodium dodecyl sulfate) and 70% formic acid, are inappropriate for use in this procedure due to the possibility of irreversible denaturation of the proteins, accompanied by a lack of immunogenicity and/or activity. Although guanidine hydrochloride and similar agents are denaturants, this denaturation is not irreversible and renaturation may occur upon removal (by dialysis, for example) or dilution of the denaturant, allowing re-formation of the immunologically and/or biologically active protein of interest. After solubilization, the protein can be separated from other bacterial proteins by standard separation techniques.

[96] Alternatively, it is possible to purify proteins from bacteria periplasm. Where the protein is exported into the periplasm of the bacteria, the periplasmic fraction of the bacteria can be isolated by cold osmotic shock in addition to other methods known to those of skill in the art (see, Ausubel et al, supra). To isolate recombinant proteins from the periplasm, the bacterial cells are centrifuged to form a pellet. The pellet is resuspended in a buffer containing 20% sucrose. To lyse the cells, the bacteria are centrifuged and the pellet is resuspended in ice-cold 5 mM MgSO₄ and kept in an ice bath for approximately 10 minutes. The cell suspension is centrifuged and the supernatant decanted and saved. The recombinant proteins present in the supernatant can be separated from the host proteins by standard separation techniques well known to those of skill in the art.

B. Purification of Proteins from Insect Cells [97] Proteins can also be purified from eukaryotic gene expression systems as described in, e.g., Fernandez and Hoeffler, Gene Expression Systems (1999). In some embodiments, baculo virus expression systems are used to isolate proteins of the invention. Recombinant baculoviruses are generally generated by replacing the polyhedrin coding sequence of a baculovirus with a gene to be expressed (e.g., encoding a polypeptide of the invention). Viruses lacking the polyhedrin gene have a unique plaque morphology making them easy to recognize. In some embodiments, a recombinant baculovirus is generated by first cloning a polynucleotide of interest into a transfer vector (e.g., a pUC based vector) such that the polynucleotide is operably linked to a polyhedrin promoter. The transfer vector is transfected with wildtype DNA into an insect cell (e.g., Sf9, Sf21 or BT1-TN-5B1-4 cells), resulting in homologous recombination and replacement of the polyhedrin gene in the wildtype viral DNA with the polynucleotide of interest. Virus can then be generated and plaque purified. Protein expression results upon viral infection of insect cells. Expressed proteins can be harvested from cell supernatant if secreted, or from cell lysates if intracellular. See, e.g., Ausubel et al. and Fernandez and Hoeffler, supra.

C. Purification of secreted proteins from mammalian cells

[98] Polypeptides of the invention, and in particular, secreted proteins of the invention can be readily purified from mammalian cells expressing the polypeptides.

Expression of the polypeptides can be the result of either transient or stable expression of the protein from a recombinant expression cassette introduced into the cells. Secreted proteins can generally be isolated using standard procedures to purify the proteins from the cell culture medium.

D. Standard Protein Separation Techniques For Purifying Proteins

1. Solubility Fractionation

[99] Often as an initial step, and if the protein mixture is complex, an initial salt fractionation can separate many of the unwanted host cell proteins (or proteins derived from the cell culture media) from the recombinant protein of interest. The preferred salt is ammonium sulfate. Ammonium sulfate precipitates proteins by effectively reducing the amount of water in the protein mixture. Proteins then precipitate on the basis of their solubility. The more hydrophobic a protein is, the more likely it is to precipitate at lower ammonium sulfate concentrations. A typical protocol is to add saturated ammonium sulfate to a protein solution so that the resultant ammonium sulfate concentration is between 20-30%. This will precipitate the most hydrophobic proteins. The precipitate is discarded (unless the protein of interest is hydrophobic) and ammonium sulfate is added to the supernatant to a concentration known to precipitate the protein of interest. The precipitate is then solubilized in buffer and the excess salt removed if necessary, through either dialysis or diafϊltration. Other methods that rely on solubility of proteins, such as cold ethanol precipitation, are well known to those of skill in the art and can be used to fractionate complex protein mixtures. 2. Size Differential Filtration

[100] Based on a calculated molecular weight, a protein of greater and lesser size can be isolated using ultrafiltration through membranes of different pore sizes (for example, Amicon or Millipore membranes). As a first step, the protein mixture is ultrafiltered through a membrane with a pore size that has a lower molecular weight cut-off than the molecular weight of the protein of interest. The retentate of the ultrafiltration is then ultrafiltered against a membrane with a molecular cut off greater than the molecular weight of the protein of interest. The recombinant protein will pass through the membrane into the filtrate. The filtrate can then be chromatographed as described below. 3. Column Chromatography

[101] The proteins of interest can also be separated from other proteins on the basis of their size, net surface charge, hydrophobicity and affinity for ligands. In addition, antibodies raised against proteins can be conjugated to column matrices and the proteins immunopurified. AU of these methods are well known in the art. [102] Immunoaffinity chromatography using antibodies raised to a variety of affinity tags such as hemagglutinin (HA), FLAG, Xpress, Myc, hexahistidine (His), glutathione S transferase (GST) and the like can be used to purify polypeptides. The His tag will also act as a chelating agent for certain metals (e.g., Ni) and thus the metals can also be used to purify His-containing polypeptides. After purification, the tag is optionally removed by specific proteolytic cleavage.

[103] It will be apparent to one of skill that chromatographic techniques can be performed at any scale and using equipment from many different manufacturers {e.g., Pharmacia Biotech).

IV. DETECTION OF POLYNUCLEOTIDES OF THE INVENTION [104] Those of skill in the art will recognize that detection of expression of polynucleotides and polypeptides of the invention has many uses. For example, as discussed herein, detection of levels of polynucleotides and polypeptides of the invention in a patient is useful for diagnosing diabetes or a predisposition for at least some of the pathological effects of diabetes. Moreover, detection of gene expression is useful to identify modulators of expression of polynucleotides and polypeptides of the invention.

[105] A variety of methods of specific DNA and RNA measurement that use nucleic acid hybridization techniques are known to those of skill in the art (see, Sambrook, supra). Some methods involve an electrophoretic separation (e.g., Southern blot for detecting DNA, and Northern blot for detecting RNA), but measurement of DNA and RNA can also be carried out in the absence of electrophoretic separation (e.g., by dot blot). Southern blot of genomic DNA (e.g., from a human) can be used for screening for restriction fragment length polymorphism (RFLP) to detect the presence of a genetic disorder affecting a polypeptide of the invention.

[106] The selection of a nucleic acid hybridization format is not critical. A variety of nucleic acid hybridization formats are known to those skilled in the art. For example, common formats include sandwich assays and competition or displacement assays. Hybridization techniques are generally described in Hames and Higgins Nucleic Acid Hybridization, A Practical Approach, IRL Press (1985); Gall and Pardue, Proc. Natl. Acad. ScL U.S.A., 63:378-383 (1969); and John et al. Nature, 223:582-587 (1969).

[107] Detection of a hybridization complex may require the binding of a signal-generating complex to a duplex of target and probe polynucleotides or nucleic acids. Typically, such binding occurs through ligand and anti-ligand interactions as between a ligand-conjugated probe and an anti-ligand conjugated with a signal. The binding of the signal generation complex is also readily amenable to accelerations by exposure to ultrasonic energy.

[108] The label may also allow indirect detection of the hybridization complex. For example, where the label is a hapten or antigen, the sample can be detected by using antibodies. In these systems, a signal is generated by attaching fluorescent or enzyme molecules to the antibodies or in some cases, by attachment to a radioactive label (see, e.g., Tijssen, "Practice and Theory of Enzyme Immunoassays " Laboratory Techniques in Biochemistry and Molecular Biology, Burdon and van Knippenberg Eds., Elsevier (1985), pp. 9-20). [109] The probes are typically labeled either directly, as with isotopes, chromophores, lumiphores, chromogens, or indirectly, such as with biotin, to which a streptavidin complex may later bind. Thus, the detectable labels used in the assays of the present invention can be primary labels (where the label comprises an element that is detected directly or that produces a directly detectable element) or secondary labels (where the detected label binds to a primary label, e.g., as is common in immunological labeling). Typically, labeled signal nucleic acids are used to detect hybridization. Complementary nucleic acids or signal nucleic acids may be labeled by any one of several methods typically used to detect the presence of hybridized polynucleotides. The most common method of detection is the use of autoradiography with H, I, S, C, or P-labeled probes or the like. [110] Other labels include, e.g., ligands that bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies that can serve as specific binding pair members for a labeled ligand. An introduction to labels, labeling procedures and detection of labels is found in Polak and Van Noorden Introduction to Immunocytochemistry, 2nd ed., Springer Verlag, NY (1997); and in Haugland Handbook of Fluorescent Probes and Research Chemicals, a combined handbook and catalogue Published by Molecular Probes, Inc. (1996).

[Ill] In general, a detector that monitors a particular probe or probe combination is used to detect the detection reagent label. Typical detectors include spectrophotometers, phototubes and photodiodes, microscopes, scintillation counters, cameras, film and the like, as well as combinations thereof. Examples of suitable detectors are widely available from a variety of commercial sources known to persons of skill in the art. Commonly, an optical image of a substrate comprising bound labeling moieties is digitized for subsequent computer analysis. [112] The amount of, for example, an RNA is measured by quantifying the amount of label fixed to the solid support by binding of the detection reagent. Typically, the presence of a modulator during incubation will increase or decrease the amount of label fixed to the solid support relative to a control incubation that does not comprise the modulator, or as compared to a baseline established for a particular reaction type. Means of detecting and quantifying labels are well known to those of skill in the art.

[113] hi some embodiments, the target nucleic acid or the probe is immobilized on a solid support. Solid supports suitable for use in the assays of the invention are known to those of skill in the art. As used herein, a solid support is a matrix of material in a substantially fixed arrangement. [114] A variety of automated solid-phase assay techniques are also appropriate. For instance, very large scale immobilized polymer arrays (VLSIP S™), i.e. Gene Chips or microarrays, available from Affymetrix, Inc. in Santa Clara, CA can be used to detect changes in expression levels of a plurality of genes involved in the same regulatory pathways simultaneously. See, Tijssen, supra., Fodor et al. (1991) Science, 251: 767- 777; Sheldon et al. (1993) Clinical Chemistry 39(4): 718-719, and Kozal et al. (1996) Nature

Medicine 2(7): 753-759. Similarly, spotted cDNA arrays (arrays of cDNA sequences bound to nylon, glass or another solid support) can also be used to monitor expression of a plurality of genes. [115] Typically, the array elements are organized in an ordered fashion so that each element is present at a specified location on the substrate. Because the array elements are at specified locations on the substrate, the hybridization patterns and intensities (which together create a unique expression profile) can be interpreted in terms of expression levels of particular genes and can be correlated with a particular disease or condition or treatment. See, e.g., Schena et al, Science 270: 467-470 (1995)) and (Lockhart et al, Nature Biotech. 14: 1675-1680 (1996)).

[116] Hybridization specificity can be evaluated by comparing the hybridization of specificity-control polynucleotide sequences to specificity-control polynucleotide probes that are added to a sample in a known amount. The specificity-control target polynucleotides may have one or more sequence mismatches compared with the corresponding polynucleotide sequences. In this manner, whether only complementary target polynucleotides are hybridizing to the polynucleotide sequences or whether mismatched hybrid duplexes are forming is determined. [117] Hybridization reactions can be performed in absolute or differential hybridization formats. In the absolute hybridization format, polynucleotide probes from one sample are hybridized to the sequences in a microarray format and signals detected after hybridization complex formation correlate to polynucleotide probe levels in a sample. In the differential hybridization format, the differential expression of a set of genes in two biological samples is analyzed. For differential hybridization, polynucleotide probes from both biological samples are prepared and labeled with different labeling moieties. A mixture of the two labeled polynucleotide probes is added to a microarray. The microarray is then examined under conditions in which the emissions from the two different labels are individually detectable. Sequences in the microarray that are hybridized to substantially equal numbers of polynucleotide probes derived from both biological samples give a distinct combined fluorescence (Shalon et al. PCT publication WO95/35505). In some embodiments, the labels are fluorescent labels with distinguishable emission spectra, such as Cy3 and Cy5 fluorophores.

[118] After hybridization, the microarray is washed to remove nonhybridized nucleic acids and complex formation between the hybridizable array elements and the polynucleotide probes is detected. Methods for detecting complex formation are well known to those skilled in the art. In some embodiments, the polynucleotide probes are labeled with a fluorescent label and measurement of levels and patterns of fluorescence indicative of complex formation is accomplished by fluorescence microscopy, such as confocal fluorescence microscopy.

[119] In a differential hybridization experiment, polynucleotide probes from two or more different biological samples are labeled with two or more different fluorescent labels with different emission wavelengths. Fluorescent signals are detected separately with different photomultipliers set to detect specific wavelengths. The relative abundances/expression levels of the polynucleotide probes in two or more samples are obtained.

[120] Typically, microarray fluorescence intensities can be normalized to take into account variations in hybridization intensities when more than one microarray is used under similar test conditions. In some embodiments, individual polynucleotide probe/target complex hybridization intensities are normalized using the intensities derived from internal normalization controls contained on each microarray.

[121] Detection of nucleic acids can also be accomplished, for example, by using a labeled detection moiety that binds specifically to duplex nucleic acids (e.g., an antibody that is specific for RNA-DNA duplexes). One example uses an antibody that recognizes DNA-RNA heteroduplexes in which the antibody is linked to an enzyme (typically by recombinant or covalent chemical bonding). The antibody is detected when the enzyme reacts with its substrate, producing a detectable product. Coutlee et al. (1989) Analytical Biochemistry 181:153-162; Bogulavski (1986) et al J. Immunol. Methods 89:123- 130; Prooijen-Knegt (1982) Exp. Cell Res. 141:397-407; Rudkin (1976) Nature 265:472-473, Stollar (1970) PNAS 65:993-1000; Ballard (1982) MoI. Immunol. 19:793-799; Pisetsky and Caster (1982) MoI. Immunol. 19:645-650; Viscidi et al. (1988) J. CHn. Microbial. 41:199- 209; and Kiney et al. (1989) J. CHn. Microbiol. 27:6-12 describe antibodies to RNA duplexes, including homo and heteroduplexes. Kits comprising antibodies specific for DNA:RNA hybrids are available, e.g., from Digene Diagnostics, Inc. (Beltsville, MD).

[122] In addition to available antibodies, one of skill in the art can easily make antibodies specific for nucleic acid duplexes using existing techniques, or modify those antibodies that are commercially or publicly available. Li addition to the art referenced above, general methods for producing polyclonal and monoclonal antibodies are known to those of skill in the art (see, e.g., Paul (ed) Fundamental Immunology, Third Edition Raven Press, Ltd., NY (1993); Coligan Current Protocols in Immunology Wiley/Greene, NY (1991); Harlow and Lane Antibodies: A Laboratory Manual Cold Spring Harbor Press, NY (1989); Stites et al. (eds.) Basic and Clinical Immunology (4th ed.) Lange Medical Publications, Los Altos, CA, and references cited therein; Goding Monoclonal Antibodies: Principles and Practice (2d ed.) Academic Press, New York, NY, (1986); and Kohler and Milstein Nature 256: 495- 497 (1975)). Other suitable techniques for antibody preparation include selection of libraries of recombinant antibodies in phage or similar vectors {see, Huse et al. Science 246:1275- 1281 (1989); and Ward et al Nature 341 :544-546 (1989)). Specific monoclonal and polyclonal antibodies and antisera will usually bind with a K_D of at least about 0.1 μM, preferably at least about 0.01 μM or better, and most typically and preferably, 0.001 μM or better.

[123] The nucleic acids used in this invention can be either positive or negative probes. Positive probes bind to their targets and the presence of duplex formation is evidence of the presence of the target. Negative probes fail to bind to the suspect target and the absence of duplex formation is evidence of the presence of the target. For example, the use of a wild type specific nucleic acid probe or PCR primers may serve as a negative probe in an assay sample where only the nucleotide sequence of interest is present. [124] The sensitivity of the hybridization assays may be enhanced through use of a nucleic acid amplification system that multiplies the target nucleic acid being detected. Examples of such systems include the polymerase chain reaction (PCR) system and the ligase chain reaction (LCR) system. Other methods recently described in the art are the nucleic acid sequence based amplification (NASBA, Cangene, Mississauga, Ontario) and Q Beta Replicase systems. These systems can be used to directly identify mutants where the PCR or LCR primers are designed to be extended or ligated only when a selected sequence is present. Alternatively, the selected sequences can be generally amplified using, for example, nonspecific PCR primers and the amplified target region later probed for a specific sequence indicative of a mutation. It is understood that various detection probes, including Taqman and molecular beacon probes can be used to monitor amplification reaction products, e.g., in real time.

[125] An alternative means for determining the level of expression of the nucleic acids of the present invention is in situ hybridization. In situ hybridization assays are well known and are generally described in Angerer et al, Methods Enzymol. 152:649-660 (1987). In an in situ hybridization assay, cells, preferentially human cells from the cerebellum or the hippocampus, are fixed to a solid support, typically a glass slide. IfDNA is to be probed, the cells are denatured with heat or alkali. The cells are then contacted with a hybridization solution at a moderate temperature to permit annealing of specific probes that are labeled. The probes are preferably labeled with radioisotopes or fluorescent reporters. [126] Single nucleotide polymorphism (SNP) analysis is also useful for detecting differences between alleles of the polynucleotides (e.g., genes) of the invention. SNPs linked to genes encoding polypeptides of the invention are useful, for instance, for diagnosis of diseases (e.g., diabetes) whose occurrence is linked to the gene sequences of the invention. For example, if an individual carries at least one SNP linked to a disease- associated allele of the gene sequences of the invention, the individual is likely predisposed for one or more of those diseases. If the individual is homozygous for a disease-linked SNP, the individual is particularly predisposed for occurrence of that disease (e.g., diabetes). In some embodiments, the SNP associated with the gene sequences of the invention is located within 300,000; 200,000; 100,000; 75,000; 50,000; or 10,000 base pairs from the gene sequence.

[127] Various real-time PCR methods including, e.g., Taqman or molecular beacon-based assays (e.g., U.S. Patent Nos. 5,210,015; 5,487,972; Tyagi et al, Nature Biotechnology 14:303 (1996); and PCT WO 95/13399 are useful to monitor for the presence of absence of a SNP. Additional SNP detection methods include, e.g., DNA sequencing, sequencing by hybridization, dot blotting, oligonucleotide array (DNA Chip) hybridization analysis, or are described in, e.g., U.S. Patent No. 6,177,249; Landegren et al, Genome Research, S:769-776 (1998); Botstein etal., Am JHuman Genetics 32:314-331 (1980); Meyers et al, Methods in Enzymology 155:501-527 (1987); Keen et al, Trends in Genetics 7:5 (1991); Myers et al, Science 230:1242-1246 (1985); and Kwok et al, Genomics 23:138- 144 (1994).

V. DETECTION OF POLYPEPTIDES OF THE INVENTION

[128] In addition to the detection of polynucleotides of the invention and gene expression using nucleic acid hybridization technology, one can also use immunoassays to detect polypeptides of the invention. Immunoassays can be used to qualitatively or quantitatively analyze polypeptides of the invention. A general overview of the applicable technology can be found in Harlow & Lane, Antibodies: A Laboratory Manual (1988).

A. Antibodies to Target Proteins or other immunogens

[129] Methods for producing polyclonal and monoclonal antibodies that react specifically with a protein of interest or other immunogen are known to those of skill in the art {see, e.g., Coligan, supra; and Harlow and Lane, supra; Stites et al, supra and references cited therein; Goding, supra; and Kohler and Milstein Nature, 256:495-497 (1975)). Such techniques include antibody preparation by selection of antibodies from libraries of recombinant antibodies in phage or similar vectors {see, Huse et al, supra; and Ward et ah, supra). For example, in order to produce antisera for use in an immunoassay, the protein of interest or an antigenic fragment thereof, is isolated as described herein. For example, a recombinant protein is produced in a transformed cell line. An inbred strain of mice or rabbits is immunized with the protein using a standard adjuvant, such as Freund's adjuvant, and a standard immunization protocol. Alternatively, a synthetic peptide derived from the sequences disclosed herein is conjugated to a carrier protein and used as an immunogen.

[130] Polyclonal sera are collected and titered against the immunogen in an immunoassay, for example, a solid phase immunoassay with the immunogen immobilized on a solid support. Polyclonal antisera with a titer of 10⁴ or greater are selected and tested for their crossreactivity against proteins other than the polypeptides of the invention or even other homologous proteins from other organisms, using a competitive binding immunoassay. Specific monoclonal and polyclonal antibodies and antisera will usually bind with a K_D of at least about 0.1 mM, more usually at least about 1 μM, preferably at least about 0.1 μM or better, and most preferably, 0.01 μM or better.

[131] A number of proteins of the invention comprising immunogens may be used to produce antibodies specifically or selectively reactive with the proteins of interest. Recombinant protein is the preferred immunogen for the production of monoclonal or polyclonal antibodies. Naturally occurring protein may also be used either in pure or impure form. Synthetic peptides made using the protein sequences described herein may also be used as an immunogen for the production of antibodies to the protein. Recombinant protein can be expressed in eukaryotic or prokaryotic cells and purified as generally described supra. The product is then injected into an animal capable of producing antibodies. Either monoclonal or polyclonal antibodies may be generated for subsequent use in immunoassays to measure the protein.

[132] Methods of production of polyclonal antibodies are known to those of skill in the art. In brief, an immunogen, preferably a purified protein, is mixed with an adjuvant and animals are immunized. The animal's immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to polypeptides of the invention. When appropriately high titers of antibody to the immunogen are obtained, blood is collected from the animal and antisera are prepared. Further fractionation of the antisera to enrich for antibodies reactive to the protein can be done if desired {see, Harlow and Lane, supra). [133] Monoclonal antibodies may be obtained using various techniques familiar to those of skill in the art. Typically, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (see, Kohler and Milstein, Eur. J. Immunol. 6:511-519 (1976)). Alternative methods of immortalization include, e.g., transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, one may isolate DNA sequences that encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells according to the general protocol outlined by Huse et ai, supra.

[134] Once target immunogen-specific antibodies are available, the immunogen can be measured by a variety of immunoassay methods with qualitative and quantitative results available to the clinician. For a review of immunological and immunoassay procedures in general see, Stites, supra. Moreover, the immunoassays of the present invention can be performed in any of several configurations, which are reviewed extensively in Maggio Enzyme Immunoassay, CRC Press, Boca Raton, Florida (1980); Tijssen, supra; and Harlow and Lane, supra. [135] Immunoassays to measure target proteins in a human sample may use a polyclonal antiserum that was raised to full-length polypeptides of the invention or a fragment thereof. This antiserum is selected to have low cross-reactivity against other proteins and any such cross-reactivity is removed by immunoabsorption prior to use in the immunoassay.

B. Immunological Binding Assays

[136] In some embodiments, a protein of interest is detected and/or quantified using any of a number of well-known immunological binding assays (see, e.g., U.S. Patents 4,366,241; 4,376,110; 4,517,288; and 4,837,168). For a review of the general immunoassays, see also Asai Methods in Cell Biology Volume 37: Antibodies in Cell Biology, Academic Press, Inc. NY (1993); Stites, supra. Immunological binding assays (or immunoassays) typically utilize a "capture agent" to specifically bind to and often immobilize the analyte (e.g., full-length polypeptides of the present invention, or antigenic subsequences thereof). The capture agent is a moiety that specifically binds to the analyte. The antibody may be produced by any of a number of means well known to those of skill in the art and as described above.

[137] Immunoassays also often utilize a labeling agent to bind specifically to and label the binding complex formed by the capture agent and the analyte. The labeling agent may itself be one of the moieties comprising the antibody/analyte complex. Alternatively, the labeling agent may be a third moiety, such as another antibody, that specifically binds to the antibody/protein complex.

[138] hi a preferred embodiment, the labeling agent is a second antibody bearing a label. Alternatively, the second antibody may lack a label, but it may, in turn, be bound by a labeled third antibody specific to antibodies of the species from which the second antibody is derived. The second antibody can be modified with a detectable moiety, such as biotin, to which a third labeled molecule can specifically bind, such as enzyme-labeled streptavidin. [139] Other proteins capable of specifically binding immunoglobulin constant regions, such as protein A or protein G, can also be used as the label agents. These proteins are normal constituents of the cell walls of streptococcal bacteria. They exhibit a strong non-immunogenic reactivity with immunoglobulin constant regions from a variety of species (see, generally, Kronval, et al. J. Immunol., 111:1401-1406 (1973); and Akerstrom, et al. J. Immunol, 135:2589-2542 (1985)).

[140] Throughout the assays, incubation and/or washing steps may be required after each combination of reagents. Incubation steps can vary from about 5 seconds to several hours, preferably from about 5 minutes to about 24 hours. The incubation time will depend upon the assay format, analyte, volume of solution, concentrations, and the like. Usually, the assays will be carried out at ambient temperature, although they can be conducted over a range of temperatures, such as 10°C to 40°C. 1. Non-Competitive Assay Formats

[141] Immunoassays for detecting proteins or analytes of interest from tissue samples may be either competitive or noncompetitive. Noncompetitive immunoassays are assays in which the amount of captured protein or analyte is directly measured. In one preferred "sandwich" assay, for example, the capture agent (e.g., antibodies specific for the polypeptides of the invention) can be bound directly to a solid substrate where it is immobilized. These immobilized antibodies then capture the polypeptide present in the test sample. The polypeptide of the invention thus immobilized is then bound by a labeling agent, such as a second labeled antibody specific for the polypeptide. Alternatively, the second antibody may lack a label, but it may, in turn, be bound by a labeled third antibody specific to antibodies of the species from which the second antibody is derived. The second can be modified with a detectable moiety, such as biotin, to which a third labeled molecule can specifically bind, such as enzyme-labeled streptavidin. 2. Competitive Assay Formats

[142] In competitive assays, the amount of protein or analyte present in the sample is measured indirectly by measuring the amount of an added (exogenous) protein or analyte displaced (or competed away) from a specific capture agent (e.g., antibodies specific for a polypeptide of the invention) by the protein or analyte present in the sample. The amount of immunogen bound to the antibody is inversely proportional to the concentration of immunogen present in the sample. In a particularly preferred embodiment, the antibody is immobilized on a solid substrate. The amount of analyte may be detected by providing a labeled analyte molecule. It is understood that labels can include, e.g., radioactive labels as well as peptide or other tags that can be recognized by detection reagents such as antibodies.

[143] Immunoassays in the competitive binding format can be used for cross- reactivity determinations. For example, the protein encoded by the sequences described herein can be immobilized on a solid support. Proteins are added to the assay and compete with the binding of the antisera to the immobilized antigen. The ability of the above proteins to compete with the binding of the antisera to the immobilized protein is compared to that of the protein encoded by any of the sequences described herein. The percent cross-reactivity for the above proteins is calculated, using standard calculations. Those antisera with less than 10% cross-reactivity with each of the proteins listed above are selected and pooled. The cross-reacting antibodies are optionally removed from the pooled antisera by imrnunoabsorption with the considered proteins, e.g., distantly related homologs.

[144] The immunoabsorbed and pooled antisera are then used in a competitive binding immunoassay as described above to compare a second protein, thought to be perhaps a protein of the present invention, to the immunogen protein, hi order to make this comparison, the two proteins are each assayed at a wide range of concentrations and the amount of each protein required to inhibit 50% of the binding of the antisera to the immobilized protein is determined. If the amount of the second protein required is less than 10 times the amount of the protein partially encoded by a sequence herein that is required, then the second protein is said to specifically bind to an antibody generated to an immunogen consisting of the target protein. 3. Other Assay Formats

[145] In some embodiments, western blot (immunoblot) analysis is used to detect and quantify the presence of a polypeptide of the invention in the sample. The technique generally comprises separating sample proteins by gel electrophoresis on the basis of molecular weight, transferring the separated proteins to a suitable solid support (such as, e.g., a nitrocellulose filter, a nylon filter, or a derivatized nylon filter) and incubating the sample with the antibodies that specifically bind the protein of interest. For example, antibodies are selected that specifically bind to the polypeptides of the invention on the solid support. These antibodies may be directly labeled or alternatively may be subsequently detected using labeled antibodies (e.g., labeled sheep anti-mouse antibodies) that specifically bind to the antibodies against the protein of interest.

[146] Other assay formats include liposome immunoassays (LIA), which use liposomes designed to bind specific molecules (e.g., antibodies) and release encapsulated reagents or markers. The released chemicals are then detected according to standard techniques (see, Monroe et al. (1986) Amer. Clin. Prod. Rev. 5:34-41).

4. Labels

[147] The particular label or detectable group used in the assay is not a critical aspect of the invention, as long as it does not significantly interfere with the specific binding of the antibody used in the assay. The detectable group can be any material having a detectable physical or chemical property. Such detectable labels have been well-developed in the field of immunoassays and, in general, most labels useful in such methods can be applied to the present invention. Thus, a label is any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Useful labels in the present invention include magnetic beads (e.g., Dynabeads™), fluorescent dyes (e.g., fluorescein isothiocyanate, Texas red, rhodamine, and the like), radiolabels (e.g., ³H, ¹²⁵1, ³⁵S, ¹⁴C, or ³²P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and colorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads.

[148] The label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art. As indicated above, a wide variety of labels may be used, with the choice of label depending on the sensitivity required, the ease of conjugation with the compound, stability requirements, available instrumentation, and disposal provisions. [149] Non-radioactive labels are often attached by indirect means. The molecules can also be conjugated directly to signal generating compounds, e.g., by conjugation with an enzyme or fluorescent compound. A variety of enzymes and fluorescent compounds can be used with the methods of the present invention and are well-known to those of skill in the art (for a review of various labeling or signal producing systems which may be used, see, e.g., U.S. Patent No. 4,391,904).

[150] Means of detecting labels are well known to those of skill in the art. Thus, for example, where the label is a radioactive label, means for detection include a scintillation counter or photographic film as in autoradiography. Where the label is a fluorescent label, it may be detected by exciting the fluorochrome with the appropriate wavelength of light and detecting the resulting fluorescence. The fluorescence may be detected visually, by means of photographic film, by the use of electronic detectors such as charge coupled devices (CCDs) or photomultipliers and the like. Similarly, enzymatic labels may be detected by providing the appropriate substrates for the enzyme and detecting the resulting reaction product. Finally simple colorimetric labels may be detected directly by observing the color associated with the label. Thus, in various dipstick assays, conjugated gold often appears pink, while various conjugated beads appear the color of the bead.

[151] Some assay formats do not require the use of labeled components. For instance, agglutination assays can be used to detect the presence of the target antibodies. In this case, antigen-coated particles are agglutinated by samples comprising the target antibodies. In this format, none of the components need to be labeled and the presence of the target antibody is detected by simple visual inspection.

VI. IDENTIFICATION OF MODULATORS OF POLYPEPTIDES OF THE

INVENTION [152] Modulators of a polypeptide of the invention, i.e. agonists or antagonists of a polypeptide's activity, or polypeptide's or polynucleotide's expression or full-length polypeptides of the invention or fragments thereof, are useful for treating a number of human diseases, including diabetes or obesity. For example, administration of modulators can be used to treat diabetic patients or prediabetic individuals to prevent progression, and therefore symptoms, associated with diabetes (including insulin resistance). Modulators of the invention can also be used to reduce obesity as well as the various diseases associated with obesity (e.g., gallbladder disease, cancer, sleep apnea, atherosclerosis, diabetes, and hypertension). In some cases, the modulators of the invention are used to regulate body physiology to reduce the chance of obesity-related diseases. For example, the modulators can be used to regulate serum lipids (total cholesterol, low-density lipoprotein (LDL), cholesterol, LDL/high density lipoprotein ratio and triglycerides).

A. Agents that Modulate Polypeptides of the Invention [153] The agents tested as modulators of polypeptides of the invention can be any small chemical compound, or a biological entity, such as a protein, sugar, nucleic acid or lipid. Essentially any chemical compound can be used as a potential modulator or ligand in the assays of the invention, although most often compounds that can be dissolved in aqueous or organic (especially DMSO-based) solutions are used. Modulators include agents designed to reduce the level of mRNA encoding a polypeptide of the invention (e.g. antisense molecules, ribozymes, DNAzymes, small inhibitory RNAs and the like) or the level of translation from an mRNA (e.g., translation blockers such as an antisense molecules that are complementary to translation start or other sequences on an mRNA molecule). Modulators of the invention also include antibodies that specific bind to and/or inhibit or activate the polypeptides of the invention. Other modulators include the polypeptides of the invention themselves, fragments thereof, or fusion proteins comprising the polypeptides or fragments thereof (e.g., in some embodiments, comprising at least 25, 50, or 100 amino acids of the polypeptide). For polypeptides of the invention that are receptors, soluble fragments of the polypeptides (i.e., lacking a transmembrane domain) can act as modulators of polypeptide signaling activity. For polypeptides of the invention that are secreted, both full length and fragments with biological activity can act as modulators. It will be appreciated that there are many suppliers of chemical compounds, including Sigma (St. Louis, MO), Aldrich (St. Louis, MO), Sigma- Aldrich (St. Louis, MO), Fluka Chemika-Biochemica Analytika (Buchs, Switzerland) and the like. [154] In some embodiments, high throughput screening methods involve providing a combinatorial chemical or peptide library containing a large number of potential therapeutic compounds (potential modulator compounds). Such "combinatorial chemical libraries" or "ligand libraries" are then screened in one or more assays, as described herein, to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. The compounds thus identified can serve as conventional "lead compounds" or can themselves be used as potential or actual therapeutics.

[155] A combinatorial chemical library is a collection of diverse chemical compounds generated by either chemical synthesis or biological synthesis, by combining a number of chemical "building blocks" such as reagents. For example, a linear combinatorial chemical library such as a polypeptide library is formed by combining a set of chemical building blocks (amino acids) in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can be synthesized through such combinatorial mixing of chemical building blocks. [156] Preparation and screening of combinatorial chemical libraries is well known to those of skill in the art. Such combinatorial chemical libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Patent 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493 (1991) and Houghton et al, Nature 354:84-88 (1991)). Other chemistries for generating chemical diversity libraries can also be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No. WO 91/19735), encoded peptides (e.g., PCT Publication WO 93/20242), random bio-oligomers (e.g., PCT Publication No. WO 92/00091), benzodiazepines (e.g., U.S. Pat. No. 5,288,514), diversomers such as hydantoins, benzodiazepines and dipeptides (Hobbs et al, Proc. Nat. Acad. ScL USA 90:6909-6913 (1993)), vinylogous polypeptides (Hagihara et al, J. Amer. Chem. Soc. 114:6568 (1992)), nonpeptidal peptidomimetics with glucose scaffolding (Hirschmann et al, J. Amer. Chem. Soc. 114:9217-9218 (1992)), analogous organic syntheses of small compound libraries (Chen et al, J. Amer. Chem. Soc. 116:2661 (1994)), oligocarbamates (Cho et al, Science 261:1303 (1993)), and/or peptidyl phosphonates (Campbell et al, J. Org. Chem. 59:658 (1994)), nucleic acid libraries (see Ausubel, Berger and Sambrook, all supra), peptide nucleic acid libraries (see, e.g., U.S. Patent 5,539,083), antibody libraries (see, e.g., Vaughn et al, Nature Biotechnology, 14(3):309-314 (1996) and PCT/US96/10287), carbohydrate libraries (see, e.g., Liang et al, Science, 274:1520-1522 (1996) and U.S. Patent 5,593,853), small organic molecule libraries (see, e.g., benzodiazepines, Baum C&EN, Jan 18, page 33 (1993); isoprenoids, U.S. Patent 5,569,588; thiazolidinones and metathiazanones, U.S. Patent 5,549,974; pyrrolidines, U.S. Patents 5,525,735 and 5,519,134; morpholino compounds, U.S. Patent 5,506,337; benzodiazepines, 5,288,514, and the like).

[157] Devices for the preparation of combinatorial libraries are commercially available (see, e.g., 357 MPS, 390 MPS, Advanced Chem Tech, Louisville KY, Symphony, Rainin, Woburn, MA, 433A Applied Biosystems, Foster City, CA, 9050 Plus, Millipore, Bedford, MA). In addition, numerous combinatorial libraries are themselves commercially available (see, e.g., ComGenex, Princeton, NJ., Tripos, Inc., St. Louis, MO, 3D Pharmaceuticals, Exton, PA, Martek Biosciences, Columbia, MD, etc.). B. Methods of Screening for Modulators of the Polypeptides of the Invention

[158] A number of different screening protocols can be utilized to identify agents that modulate the level of expression or activity of a polynucleotide of a polypeptide of the invention in cells, particularly mammalian cells, and especially human cells. In general terms, the screening methods involve screening a plurality of agents to identify an agent that modulates the activity of a polypeptide of the invention by, e.g., binding to the polypeptide, preventing an inhibitor or activator from binding to the polypeptide, increasing association of an inhibitor or activator with the polypeptide, or activating or inhibiting expression of the polypeptide. The assays can be designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays).

[159] Any cell expressing a full-length polypeptide of the invention or a fragment thereof can be used to identify modulators. In some embodiments, the cells are eukaryotic cells lines (e.g., CHO or HEK293) transformed to express a heterologous polypeptide of the invention. In some embodiments, a cell expressing an endogenous polypeptide of the invention is used in screens. In other embodiments, modulators are screened for their ability to affect insulin responses. In other embodiments, modulators are screened for their ability to effect body weight (as measured by BMI or waist-to-hip ratio) and secretion of a variety of obesity markers (e.g., leptin, IL-6 or TNF alpha), hi other embodiments, modulators are screened for their ability to effect lipid metabolism. In other embodiments, modulators are screened for their ability to effect the secretion and activity of adipogenic factors.

[160] In some embodiments, modulators of ADPN (e.g., comprising the amino acid sequence of SEQ ID NO: 2, 4, or 6), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[161] In some embodiments, modulators of ALOX5 (e.g., comprising the amino acid sequence of SEQ ID NO: 8, 10, or 12), maybe identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Enzyme assays can be carried out after contacting either purified recombinant ALOX5 protein, or an intact cell with a modulator using, e.g., arachidonic acid as a substrate or measuring the production of either LTB4 or cysteinyl leukotrienes.

[162] In some embodiments, modulators of CMAl (e.g., comprising the amino acid sequence of SEQ ID NO : 14, 15, 17, or 19), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Enzyme assays can be carried out after contacting either purified recombinant CMAl protein, or an intact cell with a modulator using e.g. angiotensin I as a substrate or measuring the production of angiotensin II. [163] In some embodiments, modulators of DUSP4 (e.g., comprising the amino acid sequence of SEQ ID NO: 21, 23, 25, or 27), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Enzyme assays can be carried out after contacting either purified recombinant DUSP4 protein, or an intact cell with a modulator and using a screening assay based on a receptor protein tyrosine phosphatase activity or phosphorylation and activity of MAPK.

[164] In some embodiments, modulators of ECHDCl (e.g., comprising the amino acid sequence of SEQ ID NO: 29, 31, 33, 35 or 37), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[165] In some embodiments, modulators of ECHDC3 (e.g., comprising the amino acid sequence of SEQ ID NO: 39 or 41), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[166] In some embodiments, modulators of HADHSC (e.g., comprising the amino acid sequence of SEQ ID NO: 43, 45, 47 or 49), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Enzyme assays can be carried out after contacting either purified recombinant HADHSC protein, or an intact cell with a modulator and using a screening assay based on dehydrogenation of 3-hydroxyacyl- CoAs to their corresponding 3-ketoacyl-CoAs activity and/or measuring NADH levels.

[167] In some embodiments, modulators of LGLL338 (e.g., comprising the amino acid sequence of SEQ ID NO: 51, 53, or 55), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[168] In some embodiments, modulators of MGCl 0946 (e.g., comprising the amino acid sequence of SEQ ID NO: 57, 58, 60, or 62), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[169] In some embodiments, modulators of NPRl (e.g., comprising the amino acid sequence of SEQ ID NO: 64, 66 or 68), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Modulators can be screened either by binding assays or methods that monitor modulator-induced fluctuation of intracellular cyclic GMP concentration or activity of protein kinase G. Modulators which bind to the NPRl can be screened by a ligand binding assay method using e.g. ANP or BNP. [170] In some embodiments, modulators of PLD3 (e.g., comprising the amino acid sequence of SEQ ID NO: 70, 72, 74 or 76), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Modulators can be screened by methods that monitor modulator-induced fluctuation of intracellular phosphatidic acid concentrations.

[171] In some embodiments, modulators of PTGER2 (e.g., comprising the amino acid sequence of SEQ ID NO: 78, 80 or 82), maybe identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Modulators can be screened by methods that monitor modulator-induced fluctuation of intracellular cyclic AMP concentrations or phosphorylation and activity of MAPK. Modulators which bind to the PTGER2 can be screened by a ligand binding assay method using e.g. prostaglandin E2.

[172] In some embodiments, modulators of PTGER3 (e.g., comprising the amino acid sequence of SEQ ID NO: 84, 86 or 88), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Modulators can be screened by methods that monitor modulator-induced fluctuation of intracellular cyclic AMP and/or calcium concentrations. Modulators which bind to the PTGER3 can be screened by a ligand binding assay method using, e.g., prostaglandin E2.

[173] hi some embodiments, modulators of PTGER4 (e.g., comprising the amino acid sequence of SEQ ID NO: 90, 92 or 94), maybe identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Modulators can be screened by methods that monitor modulator-induced fluctuation of intracellular cyclic AMP concentrations or phosphorylation and activity of MAPK. Modulators which bind to the PTGER4 can be screened by a ligand binding assay method using e.g. prostaglandin E2.

[174] hi some embodiments, modulators of RARRES2 (e.g., comprising the amino acid sequence of SEQ ID NO: 96, 97, 99 or 101), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. Modulators can be screened by methods that monitor modulator-induced fluctuation of intracellular calcium and /or cyclic AMP concentrations or phosphorylation and activation of MAPK. Modulators which bind to the RARRES2 can be screened by a ligand binding assay method using, e.g., ChemR23, the G-protein coupled receptor known to bind to RARRES2.

[175] In some embodiments, modulators of SCRN2 (e.g., comprising the amino acid sequence of SEQ ID NO: 103, 105 or 107), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. [176] In some embodiments, modulators of TLR8 (e.g., comprising the amino acid sequence of SEQ ID NO: 109, 111 or 113), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[177] In some embodiments, modulators of TM7SF2 (e.g., comprising the amino acid sequence of SEQ ID NO: 115, 117, 119, 121 or 123), may be identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays.

[178] In some embodiments, modulators of TMND (e.g., comprising the amino acid sequence of SEQ ID NO: 125, 127 or 129), maybe identified using, e.g., modulator binding assays, expression assays or promoter-reporter assays. 1. Polypeptide Binding Assays

[179] Preliminary screens can be conducted by screening for agents capable of binding to polypeptides of the invention, as at least some of the agents so identified are likely modulators of a polypeptide of the invention. Binding assays are also useful, e.g., for identifying endogenous proteins that interact with polypeptides of the invention. For example, antibodies, receptors or other molecules that bind polypeptides of the invention can be identified in binding assays.

[180] Binding assays usually involve contacting a polypeptide of the invention with one or more test agents and allowing sufficient time for the protein and test agents to form a binding complex. Any binding complexes formed can be detected using any of a number of established analytical techniques. Protein binding assays include, but are not limited to, methods that measure co-precipitation or co-migration on non-denaturing SDS- polyacrylamide gels, and co-migration on Western blots {see, e.g., Bennet, J.P. and Yamamura, H.I. (1985) "Neurotransmitter, Hormone or Drug Receptor Binding Methods," in Neurotransmitter Receptor Binding (Yamamura, H. L, et ah, eds.), pp. 61-89. Other binding assays involve the use of mass spectrometry or NMR techniques to identify molecules bound to a polypeptide of the invention or displacement of labeled substrates. The polypeptides of the invention utilized in such assays can be naturally expressed, cloned or synthesized.

[181] In addition, mammalian or yeast two-hybrid approaches {see, e.g., Bartel, P. L. et. al. Methods En∑ymol, 254:241 (1995)) can be used to identify polypeptides or other molecules that interact or bind when expressed together in a host cell.

2. Polypeptide Activity

[182] The activity of polypeptides of the invention can be assessed using a variety of in vitro and in vivo assays to determine functional, chemical, and physical effects, e.g., measuring ligand binding {e.g., radioactive or otherwise labeled ligand binding), second messengers {e.g., cAMP, cGMP, P₃, DAG, or Ca²⁺), ion flux, phosphorylation levels, transcription levels, and the like. Furthermore, such assays can be used to test for inhibitors and activators of the polypeptides of the invention. Modulators can also be genetically altered versions of polypeptides of the invention.

[183] The polypeptide of the assay will be selected from a polypeptide with substantial identity to a sequence of cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or other conservatively modified variants thereof. Generally, the amino acid sequence identity will be at least 70%, optionally at least 85%, optionally at least 90, or optionally at least 95% to the polypeptides exemplified herein. Optionally, the polypeptide of the assays will comprise a fragment of a polypeptide of the invention, such as an extracellular domain, transmembrane domain, cytoplasmic domain, ligand binding domain, subunit association domain, active site, and the like. Either a polypeptide of the invention or a domain thereof can be covalently linked to a heterologous protein to create a chimeric protein used in the assays described herein.

[184] Modulators of polypeptide activity are tested using either recombinant or naturally occurring polypeptides of the invention. The protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal, either recombinant or naturally occurring. For example, tissue slices, dissociated cells, e.g., from tissues expressing polypeptides of the invention, transformed cells, or membranes can be used. Modulation is tested using one of the in vitro or in vivo assays described herein. [185] Modulator binding to polypeptides of the invention, a domain, or chimeric protein can be tested in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. Binding of a modulator can be tested using, e.g. , changes in spectroscopic characteristics {e.g., fluorescence, absorbance, refractive index), hydrodynamic {e.g., shape), chromatographic, or solubility properties. [186] Samples or assays that are treated with a potential modulator (e.g., a

"test compound") are compared to control samples without the test compound, to examine the extent of modulation. Control samples (untreated with activators or inhibitors) are assigned a relative activity value of 100. Inhibition of the polypeptides of the invention is achieved when the activity value relative to the control is about 90%, optionally 50%, optionally 25- 0%. Activation of the polypeptides of the invention is achieved when the activity value relative to the control is 110%, optionally 150%, 200%, 300%, 400%, 500%, or 1000-2000%.

3. Expression Assays [187] Screening for a compound that modulates the expression of a polynucleotide or a polypeptide of the invention is also provided. Screening methods generally involve conducting cell-based assays in which test compounds are contacted with one or more cells expressing a polynucleotide or a polypeptide of the invention, and then detecting an increase or decrease in expression (either transcript or translation product). Assays can be performed with any cells that express a polynucleotide or a polypeptide of the invention.

[188] Expression can be detected in a number of different ways. As described infra, the expression level of a polynucleotide of the invention in a cell can be determined by probing the mRNA expressed in a cell with a probe that specifically hybridizes with a transcript (or complementary nucleic acid derived there from) of a polynucleotide of the invention. Probing can be conducted by lysing the cells and conducting Northern blots or without lysing the cells using in szYw-hybridization techniques. Alternatively, a polypeptide of the invention can be detected using immunological methods in which a cell lysate is probed with antibodies that specifically bind to the polypeptide. [189] Promoter-reporter assays can be carried out using mammalian cells transfected with a reporter gene operably linked to sequences derived from the promoter regions of genes encoding the polypeptides of the invention. The increased or decreased expression of the reporter gene can be detected in the presence and absence of the modulator. Expression of reporter genes may be detected by hybridization to a complementary nucleic acid, by using an immunological reagent, by assaying for an activity of the reporter gene product, or other methods known to those in the art

[190] The level of expression or activity of a polynucleotide or a polypeptide of the invention can be compared to a baseline value. The baseline value can be a value for a control sample or a statistical value that is representative of expression levels of a polynucleotide or a polypeptide of the invention for a control population (e.g., lean individuals as described herein) or cells (e.g., tissue culture cells not exposed to a modulator). Expression levels can also be determined for cells that do not express the polynucleotide or a polypeptide of the invention as a negative control. Such cells generally are otherwise substantially genetically the same as the test cells. [191] A variety of different types of cells can be utilized in the reporter assays. Cells that do not endogenously express a polypeptide of the invention can be prokaryotic, but are preferably eukaryotic. The eukaryotic cells can be any of the cells typically utilized in generating cells that harbor recombinant nucleic acid constructs. Exemplary eukaryotic cells include, but are not limited to, yeast, and various higher eukaryotic cells such as the HEK293, HepG2, COS, CHO and HeLa cell lines.

[192] Various controls can be conducted to ensure that an observed activity is authentic including running parallel reactions with cells that lack the reporter construct or by not contacting a cell harboring the reporter construct with test compound. Compounds can also be further validated as described below.

4. Validation

[193] Agents that are initially identified by any of the foregoing screening methods can be further tested to validate the apparent activity. Alternatively, potential modulators can be tested initially using the forgoing validation assays without preliminary screening.

[194] Modulators that are selected for further study can be tested for anti¬ diabetic effects using the "classic" insulin responsive cell line, mouse 3T3-L1 adipocytes, muscle cells such as L6 cells and the like. Cells (e.g., adipocytes or muscle cells) are pre- incubated with the modulators and tested for acute (up to 4 hours) and chronic (overnight) effects on basal and insulin-stimulated GLUT4 translocation and glucose uptake.

[195] Modulators that are selected for further study can be tested for anti- obesity effects using any adipocyte or adipogenic cell, e.g., mouse cell line 3T3-L1 adipocytes, freshly isolated rodent or human adipocytes, undifferentiated adipogenic cells and the like. Cells (e.g., adipocytes cells) are pre-incubated with the modulators and tested for acute (up to 4 hours) and chronic (overnight or longer) effects on basal and insulin-stimulated release of adipogenic factors, adipocyte cell size, leptin and TNF alpha release, and/or lipid metabolism. Undifferentiated adipogenic cells can be pre-incubated with the modulators and tested for effects on differentiation into adipocytes (including changes in differentiation markers) and/or triglyceride accumulation.

[196] The response of this increase in body weight can be determined at an organismal, tissue or cellular level. For example, increased fasting blood leptin levels are indicative of obesity. Other methods of measuring obesity include, e.g., calculation of BMI, waist-to-hip ratio, total body fat, measuring the blood levels of a variety of secreted proteins which have been shown to correlate to obesity (IL-6, TNF alpha) and measuring the fasted blood levels of free fatty acids.

[197] Following such studies, validity of the modulators is tested in suitable animal models. The basic format of such methods involves administering a lead compound identified during an initial screen to an animal that serves as a model for humans and then determining if expression of activity of a polypeptide of the invention is in fact modulated. [198] The effect of the compound will be assessed in either obese animals, diabetic animals or in diet induced insulin resistant animals. The body weight loss, blood glucose and insulin levels will be determined. The animal models utilized in validation studies generally are mammals of any kind. Specific examples of suitable animals include, but are not limited to, primates, mice and rats. Monogenic models of diabetes (e.g., ob/ob and db/db mice, Zucker rats and Zucker Diabetic Fatty rats, etc.) or polygenic models of diabetes (e.g., OLETF rats, GK rats, NSY mice, and KK mice) can be useful for validating modulation of a polypeptide of the invention in a diabetic or insulin resistant animal. In addition, transgenic animals expressing human polypeptides of the invention can be used to further validate drug candidates.

[199] Monogenic models of obesity (e.g., OLETF, tubby, mahogany, agouti, ob/ob and db/db mice etc) or polygenic models of obesity (e.g., high fat diet-induced obese animals, NZO mice, KK mice, Wellesley mice, GK rats, etc.)can be useful for validating modulation of a polypeptide of the invention in an obese animal. The most widely used criteria for assessing the efficacy of anti-obesity treatments are those from the FDA. The FDA defines a body weight loss of >5% as statistically significant compared to placebo. However, it will be appreciated that any detectable change in body weight following administration of a modulator of the invention can be considered a relevant result.

C. Solid Phase and Soluble High Throughput Assays

[200] In the high throughput assays of the invention, it is possible to screen up to several thousand different modulators or ligands in a single day. In particular, each well of a microtiter plate can be used to run a separate assay against a selected potential modulator, or, if concentration or incubation time effects are to be observed, every 5-10 wells can test a single modulator. Thus, a single standard microtiter plate can assay about 100 (e.g., 96) modulators. If 1536 well plates are used, then a single plate can easily assay from about 100 to about 1500 different compounds. It is possible to assay several different plates per day; assay screens for up to about 6,000-20,000 or more different compounds are possible using the integrated systems of the invention. In addition, microfluidic approaches to reagent manipulation can be used.

[201] A molecule of interest (e.g., a polypeptide or polynucleotide of the invention, or a modulator thereof) can be bound to the solid-state component, directly or indirectly, via covalent or non-covalent linkage, e.g., via a tag. The tag can be any of a variety of components. In general, a molecule that binds the tag (a tag binder) is fixed to a solid support, and the tagged molecule of interest is attached to the solid support by interaction of the tag and the tag binder. [202] A number of tags and tag binders can be used, based upon known molecular interactions well described in the literature. For example, where a tag has a natural binder, for example, biotin, protein A, or protein G, it can be used in conjunction with appropriate tag binders (avidin, streptavidin, neutravidin, the Fc region of an immunoglobulin, poly-His, etc.) Antibodies to molecules with natural binders such as biotin are also widely available and appropriate tag binders (see, SIGMA Immunochemicals 1998 catalogue SIGMA, St. Louis MO).

[203] Similarly, any haptenic or antigenic compound can be used in combination with an appropriate antibody to form a tag/tag binder pair. Thousands of specific antibodies are commercially available and many additional antibodies are described in the literature. For example, in one common configuration, the tag is a first antibody and the tag binder is a second antibody that recognizes the first antibody. In addition to antibody- antigen interactions, receptor-ligand interactions are also appropriate as tag and tag-binder pairs, such as agonists and antagonists of cell membrane receptors (e.g., cell receptor-ligand interactions such as transferrin, c-kit, viral receptor ligands, cytokine receptors, chemokine receptors, interleukin receptors, immunoglobulin receptors and antibodies, the cadherin family, the integrin family, the selectin family, and the like; see, e.g., Pigott & Power, The Adhesion Molecule Facts Book I (1993)). Similarly, toxins and venoms, viral epitopes, hormones (e.g., opiates, steroids, etc.), intracellular receptors (e.g., which mediate the effects of various small ligands, including steroids, thyroid hormone, retinoids and vitamin D; peptides), drugs, lectins, sugars, nucleic acids (both linear and cyclic polymer configurations), oligosaccharides, proteins, phospholipids and antibodies can all interact with various cell receptors.

[204] Synthetic polymers, such as polyurethanes, polyesters, polycarbonates, polyureas, polyamides, polyethyleneimines, polyarylene sulfides, polysiloxanes, polyimides, and polyacetates can also form an appropriate tag or tag binder. Many other tag/tag binder pairs are also useful in assay systems described herein, as would be apparent to one of skill upon review of this disclosure.

[205] Common linkers such as peptides, polyethers, and the like can also serve as tags, and include polypeptide sequences, such as poly-gly sequences of between about 5 and 200 amino acids. Such flexible linkers are known to those of skill in the art. For example, ρoly(ethelyne glycol) linkers are available from Shearwater Polymers, Inc., Huntsville, Alabama. These linkers optionally have amide linkages, sulfhydryl linkages, or heterofunctional linkages. [206] Tag binders are fixed to solid substrates using any of a variety of methods currently available. Solid substrates are commonly derivatized or functionalized by exposing all or a portion of the substrate to a chemical reagent that fixes a chemical group to the surface that is reactive with a portion of the tag binder. For example, groups that are suitable for attachment to a longer chain portion would include amines, hydroxyl, thiol, and carboxyl groups. Amino alkylsilanes and hydroxyalkylsilanes can be used to functionalize a variety of surfaces, such as glass surfaces. The construction of such solid phase biopolymer arrays is well described in the literature {see, e.g., Merrifield, J. Am. Chem. Soc. 85:2149- 2154 (1963) (describing solid phase synthesis of, e.g., peptides); Geysen et al, J. Immun. Meth. 102:259-274 (1987) (describing synthesis of solid phase components on pins); Frank and Doling, Tetrahedron 44:60316040 (1988) (describing synthesis of various peptide sequences on cellulose disks); Fodor et al, Science, 251:767-777 (1991); Sheldon et al, Clinical Chemistry 39(4):718-719 (1993); and Kozal et al, Nature Medicine 2(7):753759 (1996) (all describing arrays of biopolymers fixed to solid substrates). Non-chemical approaches for fixing tag binders to substrates include other common methods, such as heat, cross-linking by UV radiation, and the like.

[207] The invention provides in vitro assays for identifying, in a high throughput format, compounds that can modulate the expression or activity of a polypeptide of the invention. Control reactions that measure activity of a polypeptide of the invention in a cell in a reaction that does not include a potential modulator are optional, as the assays are highly uniform. Such optional control reactions are appropriate and increase the reliability of the assay. Accordingly, in some embodiments, the methods of the invention include such a control reaction. For each of the assay formats described, "no modulator" control reactions that do not include a modulator provide a background level of binding activity. [208] In some assays it will be desirable to have positive controls. At least two types of positive controls are appropriate. First, a known activator of a polypeptide or a polynucleotide of the invention can be incubated with one sample of the assay, and the resulting increase in signal resulting from an increased expression level or activity of a polypeptide or a polynucleotide of the invention are determined according to the methods herein. Second, a known inhibitor of a polypeptide or a polynucleotide of the invention can be added, and the resulting decrease in signal for the expression or activity of a polypeptide or a polynucleotide of the invention can be similarly detected. It will be appreciated that modulators can also be combined with activators or inhibitors to find modulators that inhibit the increase or decrease that is otherwise caused by the presence of the known modulator of a polypeptide or a polynucleotide of the invention.

VII. COMPOSITIONS, KITS AND INTEGRATED SYSTEMS

[209] The invention provides compositions, kits and integrated systems for practicing the assays described herein using nucleic acids or polypeptides of the invention, antibodies, etc.

[210] The invention provides assay compositions for use in solid phase assays; such compositions can include, for example, one or more nucleic acids encoding a polypeptide of the invention immobilized on a solid support, and a labeling reagent. In each case, the assay compositions can also include additional reagents that are desirable for hybridization. Modulators of expression or activity of a polypeptide of the invention can also be included in the assay compositions.

[211] The invention also provides kits for carrying out the assays of the invention. The kits typically include a probe that comprises (1) an antibody that specifically binds to a polypeptide of the invention or (2) a polynucleotide sequence encoding at least a fragment of such polypeptides, and a label for detecting the presence of the probe. The kits may include at least one polynucleotide sequence encoding a polypeptide of the invention. Kits can include any of the compositions noted above, and optionally further include additional components such as instructions to practice a high-throughput method of assaying for an effect on expression of the genes encoding a polypeptide of the invention, or on activity of a polypeptide of the invention, one or more containers or compartments (e.g., to hold the probe, labels, or the like), a control modulator of the expression or activity of a polypeptide of the invention, a robotic armature for mixing kit components or the like. [212] The invention also provides integrated systems for high-throughput screening of potential modulators for an effect on the expression or activity of a polypeptide of the invention. The systems can include a robotic armature which transfers fluid from a source to a destination, a controller which controls the robotic armature, a label detector, a data storage unit which records label detection, and an assay component such as a microtiter dish comprising a well having a reaction mixture or a substrate comprising a fixed nucleic acid or immobilization moiety.

[213] A number of robotic fluid transfer systems are available, or can easily be made from existing components. For example, a Zymate XP (Zymark Corporation; Hopkinton, MA) automated robot using a Microlab 2200 (Hamilton; Reno, NV) pipetting station can be used to transfer parallel samples to 96 well microtiter plates to set up several parallel simultaneous binding assays.

[214] Optical images viewed (and, optionally, recorded) by a camera or other recording device (e.g., a photodiode and data storage device) are optionally further processed in any of the embodiments herein, e.g., by digitizing the image and storing and analyzing the image on a computer. A variety of commercially available peripheral equipment and software is available for digitizing, storing and analyzing a digitized video or digitized optical image.

[215] One conventional system carries light from the specimen field to a cooled charge-coupled device (CCD) camera, in common use in the art. A CCD camera includes an array of picture elements (pixels). The light from the specimen is imaged on the CCD. Particular pixels corresponding to regions of the specimen (e.g., individual hybridization sites on an array of biological polymers) are sampled to obtain light intensity readings for each position. Multiple pixels are processed in parallel to increase speed. The apparatus and methods of the invention are easily used for viewing any sample, e.g., by fluorescent or dark field microscopic techniques.

VIII. ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS

[216] Modulators of the polypeptides of the invention (e.g., antagonists or agonists including polypeptides of the invention, fragments thereof, or fusions comprising the polypeptides or fragments which have antagonist activity or an additive effect on overall polypeptide activity) can be administered directly to the mammalian subject (typically in need thereof due to a pre-diabetic, diabetic or obese condition) for modulation of activity of a polypeptide of the invention in vivo. Administration is by any of the routes normally used for introducing a modulator compound into ultimate contact with the tissue to be treated and is well known to those of skill in the art. Although more than one route can be used to administer a particular composition, a particular route can often provide a more immediate and more effective reaction than another route. [217] The pharmaceutical compositions of the invention may comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations of pharmaceutical compositions of the present invention {see, e.g., Remington 's Pharmaceutical Sciences, 17^th ed. 1985)).

[218] The modulators (e.g., agonists or antagonists) of the expression or activity of a polypeptide of the invention, alone or in combination with other suitable components, can be prepared for injection or for use in a pump device. Pump devices (also known as "insulin pumps") are commonly used to administer insulin to patients and therefore can be easily adapted to include compositions of the present invention. Manufacturers of insulin pumps include Animas, Disetronic and MiniMed.

[219] The modulators (e.g., agonists or antagonists) of the expression or activity of a polypeptide of the invention, alone or in combination with other suitable components, can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.

[220] Formulations suitable for administration include aqueous and non¬ aqueous solutions, isotonic sterile solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, orally, nasally, topically, intravenously, intraperitoneally, or intrathecally. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. The modulators can also be administered as part of a prepared food or drug.

[221] The dose administered to a patient, in the context of the present invention should be sufficient to induce a beneficial response in the subject over time. The optimal dose level for any patient will depend on a variety of factors including the efficacy of the specific modulator employed, the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the case of diabetes. It is recommended that the daily dosage of the modulator be determined for each individual patient by those skilled in the art in a similar way as for known insulin compositions. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound or vector in a particular subject.

[222] In determining the effective amount of the modulator to be administered a physician may evaluate circulating plasma levels of the modulator, modulator toxicity, and the production of anti-modulator antibodies. In general, the dose equivalent of a modulator is from about 1 ng/kg to 10 mg/kg for a typical subject.

[223] For administration, modulators of the present invention can be administered at a rate determined by the LD-50 of the modulator, and the side-effects of the modulator at various concentrations, as applied to the mass and overall health of the subject. Administration can be accomplished via single or divided doses.

[224] The compounds of the present invention can also be used effectively in combination with one or more additional active agents depending on the desired target therapy (see, e.g., Turner, N. et al. Prog. Drug Res. (1998) 51: 33-94; Hafmer, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). A number of studies have investigated the benefits of combination therapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol. Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, C. W.,(ed.), Current Therapy In Endocrinology And Metabolism, 6th Edition (Mosby - Year Book, Inc., St. Louis, MO 1997); Chiasson, J. et al., Ann. Intern. Med. (1994) 121 : 928-935; Coniff, R. et al., Clin. Ther. (1997) 19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. et al., Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82(12A): 3U-17U). These studies indicate that modulation of diabetes, among other diseases, can be further improved by the addition of a second agent to the therapeutic regimen. Combination therapy includes administration of a single pharmaceutical dosage formulation that contains a modulator of the invention and one or more additional active agents, as well as administration of a modulator and each active agent in its own separate pharmaceutical dosage formulation. For example, a modulator and a thiazolidinedione can be administered to the human subject together in a single oral dosage composition, such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations. Where separate dosage formulations are used, a modulator and one or more additional active agents can be administered at essentially the same time (i.e., concurrently), or at separately staggered times (i.e., sequentially). Combination therapy is understood to include all these regimens. [225] One example of combination therapy can be seen in treating pre- diabetic individuals (e.g., to prevent progression into type 2 diabetes) or diabetic individuals (or treating diabetes and its related symptoms, complications, and disorders), wherein the modulators can be effectively used in combination with, for example, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide); biguanides (such as metformin); a PPAR beta delta agonist; a ligand or agonist of PPAR gamma such as thiazolidinediones (such as ciglitazone, pioglitazone (see, e.g., U.S. Patent No. 6,218,409), troglitazone, and rosiglitazone (see, e.g., U.S. Patent No. 5,859,037)); PPAR alpha agonists such as clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA-SO4); antiglucocorticoids; TNFα inhibitors; α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose); amylin and amylin derivatives (such as pramlintide, (see, also, U.S. Patent Nos. 5,902,726; 5,124,314; 5,175,145 and 6,143,718.)); insulin secretogogues (such as repaglinide, gliquidone, and nateglinide (see, also, U.S. Patent Nos. 6,251,856; 6,251,865; 6,221,633; 6,174,856)), and insulin. [226] The modulators of the invention can also be combined with anti- obesity drugs (e.g., Xenical (Orlistat), Merida (Sibutramine) or Adipex-P (Phentermine)) or appetite-suppressing drugs.

IX. GENE THERAPY

[227] Conventional viral and non- viral based gene transfer methods can be used to introduce nucleic acids encoding engineered amino acid sequences comprising the polypeptides of the invention in mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding amino acid sequences comprising polypeptides of the invention to cells in vitro. In some embodiments, the nucleic acids encoding amino acid sequences comprising polypeptides of the invention are administered for in vivo or ex vivo gene therapy uses. Non- viral vector delivery systems include DNA plasmids, naked nucleic acid, and nucleic acid complexed with a delivery vehicle such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Feigner, TIBTECH 11 :211-217 (1993); Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon, TIBTECH 11:167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10):l 149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(l):31-44 (1995); Haddada et ah, in Current Topics in Microbiology and Immunology Doerfler and Bόhm (eds) (1995); and Yu et al, Gene Therapy 1 : 13-26 (1994).

[228] Methods of non- viral delivery of nucleic acids encoding engineered polypeptides of the invention include lipofection, microinjection, biolistics, virosomes, liposomes, irnmunoliposom.es, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g., US 5,049,386, US 4,946,787; and US 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91/17424, WO 91/16024. Delivery can be to cells (ex vivo administration) or target tissues (in vivo administration).

[229] The preparation of lipid:nucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al, Cancer Gene Ther. 2:291-297 (1995); Behr et al, Bioconjugate Chem. 5:382-389 (1994); Remy et al, Bioconjugate Chem. 5:647- 654 (1994); Gao et al, Gene Therapy 2:710-722 (1995); Ahmad et al, Cancer Res. 52:4817- 4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787).

[230] The use of RNA or DNA viral based systems for the delivery of nucleic acids encoding engineered polypeptides of the invention take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro and the modified cells are administered to patients (ex vivo). Conventional viral based systems for the delivery of polypeptides of the invention could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Viral vectors are currently the most efficient and versatile method of gene transfer in target cells and tissues. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues.

[231] The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lenti viral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of czs-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum ex¬ acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof {see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992); Johann et al, J. Virol. 66:1635-1640 (1992); Sommerfelt et al, Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al, J. Virol. 65:2220-2224 (1991); PCT/US94/05700).

[232] In applications where transient expression of the polypeptides of the invention is preferred, adenoviral based systems are typically used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system. Adeno-associated virus ("AAV") vectors are also used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Patent No. 4,797,368; WO 93/24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest.

94:1351 (1994)). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No. 5,173,414; Tratschin et al, MoI Cell Biol. 5:3251-3260 (1985); Tratschin, et al, Mol Cell. Biol 4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al, J. Virol. 63:03822-3828 (1989). [233] pLASN and MFG-S are examples are retroviral vectors that have been used in clinical trials (Dunbar et al, Blood 85:3048-305 (1995); Kohn et al, Nat. Med. 1:1017-102 (1995); Malech et α/., PNAS 94:22 12133-12138 (1997)). PA317/pLASN was the first therapeutic vector used in a gene therapy trial. (Blaese et al, Science 270:475-480 (1995)). Transduction efficiencies of 50% or greater have been observed for MFG-S packaged vectors. (Ellem et al, Immunol Immunother. 44(l):10-20 (1997); Dranoff et al, Hum. Gene Ther. 1:111-2 (1997).

[234] Recombinant adeno-associated virus vectors (rAAV) are a promising alternative gene delivery systems based on the defective and nonpathogenic parvovirus adeno-associated type 2 virus. AU vectors are derived from a plasmid that retains only the AAV 145 bp inverted terminal repeats flanking the transgene expression cassette. Efficient gene transfer and stable transgene delivery due to integration into the genomes of the transduced cell are key features for this vector system. (Wagner et al, Lancet 351:9117 1702- 3 (1998), Kearns et al, Gene Ther. 9:748-55 (1996)). [235] Replication-deficient recombinant adenoviral vectors (Ad) can be engineered such that a transgene replaces the Ad EIa, EIb, and E3 genes; subsequently the replication defector vector is propagated in human 293 cells that supply deleted gene function in trans. Ad vectors can transduce multiply types of tissues in vivo, including nondividing, differentiated cells such as those found in the liver, kidney and muscle system tissues. Conventional Ad vectors have a large carrying capacity. An example of the use of an Ad vector in a clinical trial involved polynucleotide therapy for antitumor immunization with intramuscular injection (Sterman et al, Hum. Gene Ther. 7:1083-9 (1998)). Additional examples of the use of adenovirus vectors for gene transfer in clinical trials include Rosenecker et al, Infection 24:1 5-10 (1996); Sterman et al, Hum. Gene Ther. 9:7 1083- 1089 (1998); Welsh et al, Hum. Gene Ther. 2:205-18 (1995); Alvarez et al, Hum. Gene Ther. 5:597-613 (1997); Topf et al, Gene Ther. 5:507-513 (1998); Sterman et al, Hum. Gene Ther. 7:1083-1089 (1998).

[236] Packaging cells are used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and ψ2 cells or P A317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by producer cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the protein to be expressed. The missing viral functions are supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line is also infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. [237] In many gene therapy applications, it is desirable that the gene therapy vector be delivered with a high degree of specificity to a particular tissue type. A viral vector is typically modified to have specificity for a given cell type by expressing a ligand as a fusion protein with a viral coat protein on the viruses outer surface. The ligand is chosen to have affinity for a receptor known to be present on the cell type of interest. For example, Han et al, PNAS 92:9747-9751 (1995), reported that Moloney murine leukemia virus can be modified to express human heregulin fused to gp70, and the recombinant virus infects certain human breast cancer cells expressing human epidermal growth factor receptor. This principle can be extended to other pairs of virus expressing a ligand fusion protein and target cell expressing a receptor. For example, filamentous phage can be engineered to display antibody fragments (e.g., FAB or Fv) having specific binding affinity for virtually any chosen cellular receptor. Although the above description applies primarily to viral vectors, the same principles can be applied to nonviral vectors. Such vectors can be engineered to contain specific uptake sequences thought to favor uptake by specific target cells.

[238] Gene therapy vectors can be delivered in vivo by administration to an individual patient, typically by systemic administration (e.g., intravenous, intraperitoneal, intramuscular, subdermal, or intracranial infusion) or topical application, as described below. Alternatively, vectors can be delivered to cells ex vivo, such as cells explanted from an individual patient (e.g., lymphocytes, bone marrow aspirates, tissue biopsy) or universal donor hematopoietic stem cells, followed by reimplantation of the cells into a patient, usually after selection for cells which have incorporated the vector.

[239] Ex vivo cell transfection for diagnostics, research, or for gene therapy (e.g., via re-infusion of the transfected cells into the host organism) is well known to those of skill in the art. In some embodiments, cells are isolated from the subject organism, transfected with a nucleic acid (gene or cDNA) encoding a polypeptides of the invention, and re-infused back into the subject organism (e.g., patient). Various cell types suitable for ex vivo transfection are well known to those of skill in the art {see, e.g., Freshney et al., Culture of Animal Cells, A Manual of Basic Technique (3rd ed. 1994)) and the references cited therein for a discussion of how to isolate and culture cells from patients). [240] In one embodiment, stem cells are used in ex vivo procedures for cell transfection and gene therapy. The advantage to using stem cells is that they can be differentiated into other cell types in vitro, or can be introduced into a mammal (such as the donor of the cells) where they will engraft in the bone marrow. Methods for differentiating CD34+ cells in vitro into clinically important immune cell types using cytokines such a GM- CSF, IFN-γ and TNF-α are known (see Inaba et al, J. Exp. Med. 176:1693-1702 (1992)).

[241] Stem cells are isolated for transduction and differentiation using known methods. For example, stem cells are isolated from bone marrow cells by panning the bone marrow cells with antibodies which bind unwanted cells, such as CD4+ and CD8+ (T cells), CD45+ (panB cells), GR-I (granulocytes), and lad (differentiated antigen presenting cells) (see Inaba et al, J. Exp. Med. 176:1693-1702 (1992)).

[242] Vectors (e.g., retroviruses, adenoviruses, liposomes, etc.) containing therapeutic nucleic acids can be also administered directly to the organism for transduction of cells in vivo. Alternatively, naked DNA can be administered. Administration is by any of the routes normally used for introducing a molecule into ultimate contact with blood or tissue cells. Suitable methods of administering such nucleic acids are available and well known to those of skill in the art, and, although more than one route can be used to administer a particular composition, a particular route can often provide a more immediate and more effective reaction than another route. [243] Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present invention, as described below (see, e.g., Remington 's Pharmaceutical Sciences, 17th ed., 1989).

X. DIAGNOSIS OF OBESITY AND/OR DIABETES

[244] The present invention also provides methods of diagnosing diabetes or obesity, or a predisposition of at least some of the pathologies of diabetes and/or obesity. Diagnosis can involve determination of a genotype of an individual (e.g., with SNPs) and comparison of the genotype with alleles known to have an association with the occurrence of obesity and/or diabetes. Alternatively, diagnosis also involves determining the level of a polypeptide or polynucleotide of the invention in a patient and then comparing the level to a baseline or range. Typically, the baseline value is representative of a polypeptide or polynucleotide of the invention in a healthy (e.g., lean) person. [245] As discussed above, variation of levels (e.g., low or high levels) of a polypeptide or polynucleotide of the invention compared to the baseline range indicates that the patient is either obese, at risk for becoming obese, diabetic or at risk of developing at least some of the pathologies of diabetes (e.g., pre-diabetic). The level of a polypeptide in a lean individual can be a reading from a single individual, but is typically a statistically relevant average from a group of lean individuals. The level of a polypeptide in a lean individual can be represented by a value, for example in a computer program.

[246] In some embodiments, the level of polypeptide or polynucleotide of the invention is measured by taking a blood, urine or tissue sample from a patient and measuring the amount of a polypeptide or polynucleotide of the invention in the sample using any number of detection methods, such as those discussed herein. For instance, fasting and fed blood or urine levels can be tested.

[247] In some embodiments, the baseline level and the level in a lean sample from an individual, or at least two samples from the same individual differ by at least about 5%, 10%, 20%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500%, 1000% or more. In some embodiments, the sample from the individual is greater by at least one of the above- listed percentages relative to the baseline level. In some embodiments, the sample from the individual is lower by at least one of the above-listed percentages relative to the baseline level. [248] In some embodiments, the level of a polypeptide or polynucleotide of the invention is used to monitor the effectiveness of either anti-obese therapies such as orlistat or sibutramine, or, antidiabetic therapies such as thiazolidinediones, metformin, sulfonylureas and other standard therapies. In some embodiments the activity or expression of a polypeptide or polynucleotide of the invention will be measured prior to and after treatment of an obese patient with antiobese therapies, or, diabetic or pre-diabetic patients with antidiabetic therapies as a surrogate marker of clinical effectiveness. For example, the greater the reduction in expression or activity of a polypeptide of the invention indicates greater effectiveness.

[249] Glucose/insulin tolerance tests can also be used to detect the effect of glucose levels on levels of a polypeptide or polynucleotide of the invention, m glucose tolerance tests, the patient's ability to tolerate a standard oral glucose load is evaluated by assessing serum and urine specimens for glucose levels. Blood samples are taken before the glucose is ingested, glucose is given by mouth, and blood or urine glucose levels are tested at set intervals after glucose ingestion. Similarly, meal tolerance tests can also be used to detect the effect of insulin or food, respectively, on levels of a polypeptide or polynucleotide of the invention.

[250] Body weight or other indicators of obesity can also be used to detect the effect of modulating the levels of a polypeptide or polynucleotide of the invention. Measurement of a subject's response can be evaluated by assessing serum for altered levels of obesity-associated gene products, e.g., leptin, TNF alpha or IL-6.

[251] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. [252] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

EXAMPLES

[253] The following examples are offered to illustrate, but not to limit the claimed invention.

[254] In either obese insulin-resistant or type II diabetics, peripheral tissues, especially muscle and fat, are known to have an impaired ability to respond to insulin and hence to take up glucose. This defect in glucose metabolism is usually compensated for by increased secretion of insulin from the pancreas, thereby maintaining normal glucose levels. The majority of glucose disposal occurs in the muscle. A number of obese insulin resistant patients will progress to overt diabetics with time. The molecular defects underlying this peripheral insulin resistance in both the obese and type II diabetics are not well defined. Genes in muscle or fat whose expression is altered in either or both the obese or type II diabetics when compared to lean individuals can be causative genes for either obesity, insulin resistance and/or diabetes and are able to predict the transition to diabetes. Modulators of such genes have the ability to reverse obesity, insulin resistance and restore normal insulin sensitivity, thereby improving whole body glucose homeostasis including for example insulin secretion. Modulators of such genes also have the ability to be used to pre-empt the transition from obesity-induced insulin resistance to diabetes. Modulators of such genes also have the ability to be used to reverse metabolic obesity-related diseases such as cardiovascular disease, hypertension or obesity-related cancer. [255] The molecular mechanism by which thiazolidinediones (TZDs) cause an increase in peripheral insulin sensitivity was studied. Genes in muscle or fat whose expression is altered by TZDs may lie on a pathway leading from TZD treatment to increased insulin sensitivity. Modulators of such genes can elicit the same effect as TZD treatment. Moreover, such modulators can lack some of the side effects of TZD. Gene expression profiling in cultures of primary human adipocytes treated with either pioglitazone or rosiglitazone were used to identify genes important for TZD action and therefore treatment of obesity, diabetes and/or insulin resistance.

[256] Gene expression profiling was performed on tissue samples (subcutaneous adipose samples) obtained from lean, obese and diabetic individuals. Two studies were performed. In the first study, samples were isolated from all individuals after a 5 hour hyperinsulinemic euglycemic clamp.

[257] In the second study, subcutaneous adipose samples were obtained from lean (BMK 25) and obese (BMI>30) individuals after an overnight fast. [258] In a third study samples were obtained from human subcutaneous and omental adipose tissues. Genes expressed only, or enriched, in fat can lie on pathways involved in insulin sensitivity, appetite suppression or lipid metabolism in the adipose itself or other peripheral tissues (e.g., muscle, liver, brain). For all tissue samples mRNA was isolated from these adipose samples and converted to cRNA by standard procedures. The gene expression profile for each individual was determined by hybridization of cRNA to commercial and custom synthesized Affymetrix chips.

[259] Gene expression profile differences were calculated as follows. The expression level of a particular gene is indicated by its 'signal intensity'. The raw data was analyzed by a statistical test to remove Outliers'. The mean 'signal intensity' was then calculated from the signal intensities for all individuals in a particular treatment group.

Genes were determined to be changed in the first two studies by calculating the Students t test statistic between the two conditions and selecting those with t less than or equal to 0.05. The fold change was determined as the ratio of mean signal intensity in condition 2 to the mean signal intensity in condition 1. In the first study three comparisons was undertaken: diabetics (condition 1) versus leans (condition 2), obese (condition 1) versus lean (condition 2) and diabetics (condition 1) versus obese (condition 2). The second study comparison is lean (condition 1) versus obese (condition 2). The third comparison is identification of fat specific or fat enriched genes when comparing the expression profile of human subcutaneous and omental adipose tissues to at last 12 other human adult tissues. Genes were determined to be meeting the criteria cut-off when the mean signal intensity of the human adipose samples was 3 fold greater than the mean signal intensity of all the other human adult tissues profiled or called present only in the adipose samples and absent in all others by the Affymetrix software program.

ADPN

[260] Probe set 233030 detects ADPN nucleic acid sequences. Expression of ADPN transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[261] ADPN was also evaluated using real-time PCR. The results further show that ADPN is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[262] Probe set 233030 detects ADPN nucleic acid sequences. Expression of ADPN transcripts was decreased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients. [263] ADPN was also evaluated using real-time PCR. The results further show that ADPN is significantly under-expressed in subcutaneous adipose from obese individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean obese expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[264] ADPN contains the following protein domains (designated with reference to SEQ ID NO:2): Patatin-like phospholipase (PF01734) at amino acids 10 to 179. Adiponutrin is a newly identified nonsecreted adipocyte protein regulated by changes in energy balance in rodents (Baulande, S. et ah, J Biol Chem., 276:33336-44 (2001)).

ALOX5

[265] Probe set 204446 detects ALOX5 nucleic acid sequences. Expression of ALOX5 transcripts was increased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[266] ALOX5 was also evaluated using real-time PCR. The results further show that ALOX5 is significantly over-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[267] ALOX5 contains the following protein domains (designated with reference to SEQ ID NO:8): PLAT/LH2 domain (PF01477) at amino acids 2 to 115; and Lipoxygenase (PF00305) at amino acids 125 to 666. The leukotrienes arise from oxidative metabolism of arachidonic acid through the action of ALOX5, leading to the unstable allylic epoxide leukotriene A4. This intermediate represents the substrate for two different specific enzymes, namely leukotriene A4-hydrolase and leukotriene C4-synthase, generating LTB4 and cysteinyl leukotrienes, respectively. LTB(4) is a potent chemotactic and chemokinetic agent for a variety of leukocytes whereas the cysteinyl-leukotrienes C, D(4) and E(4) are known mediators of vascular permeability and smooth muscle contraction (Werz, O., Curr Drug Targets Inflamm Allergy 1 :23-44 (2002)).

CMAl

[268] Probe set 214533 detects CMAl nucleic acid sequences. Expression of

CMAl transcripts was increased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[269] CMAl was also evaluated using real-time PCR. The results further show that CMAl is significantly over-expressed in subcutaneous adipose from obese individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean obese expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[270] CMAl contains the following protein domains (designated with reference to SEQ ID NO: 14): Signal peptide at amino acids 1 to 19; and Trypsin (PF00089) at amino acids 22 to 240. A soluble active secreted form of CMAl has been detected (Caughey, GM. Et al, J Biol Chem. 1991 JuI 15;266(20):12956-63) and this is displayed in SEQ ID NO: 15. CMAl is a proteinase and is found highly expressed in mast cells and thought to function in the degradation of the extracellular matrix, the regulation of submucosal gland secretion, and the generation of vasoactive peptides. In the heart and blood vessels, CMAl is largely responsible for converting angiotensin I to the vasoactive peptide angiotensin II. Angiotensin II has been implicated in blood pressure control and in the pathogenesis of hypertension, cardiac hypertrophy, and heart failure.

DUSP4

[271] Probe set 204014 detects DUSP4 nucleic acid sequences. Expression of DUSP4 transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[272] DUSP4 was also evaluated using real-time PCR. The results further show that DUSP4 is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[273] Probe set 204014 detects DUSP4 nucleic acid sequences. Expression of DUSP4 transcripts was decreased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[274] DUSP4 was also evaluated using real-time PCR. The results further show that DUSP4 is significantly under-expressed in subcutaneous adipose from obese individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean obese expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[275] Probe set 204014 detects DUSP4 nucleic acid sequences. Expression of DUSP4 transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[276] DUSP4 was also evaluated using real-time PCR. The results further show that DUSP4 is significantly over-expressed in adipose tissues when compared to all other human adult tissues.

"Fold Change" indicates the fold expression calculated as the ratio of the mean adipose tissues expression/ mean other tissues expression. Numbers in parentheses indicates the number of human adult tissue samples analyzed by real-time PCR.

[277] DUSP4 contains the following protein domains (designated with reference to SEQ ID NO:21): Dual specificity phosphatase, catalytic domain (PF00782) at amino acids 195 to 333; Rhodanese-like domain (PF00581) at amino acids 33 to 153; and Protein-tyrosine phosphatase (PFOOl 02) at amino acids 159 to 337. DUSP4 is a member of the dual specificity protein phosphatase subfamily. DUSP4 has been reported to negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation. Two alternatively spliced transcript variants, encoding distinct isoforms, have been observed for this gene.

ECHDCl

[278] Probe set 223087 detects ECHDCl nucleic acid sequences. Expression of ECHDCl transcripts was decreased in patients with insulin resistance compared to normal patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Corr Co-efficient" indicates the relationship between glucose disposal rate (Rd) and signal intensities. A positive co-efficient indicates down regulation whereas a negative co-efficient indicates up regulation of the gene with increasing insulin resistance; "n" indicates number of patient samples.

[279] Probe set 223087 detects ECHDCl nucleic acid sequences. Expression of ECHDCl transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[280] Probe set 223087 detects ECHDCl nucleic acid sequences. Expression of ECHDCl transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[281] ECHDCl was also evaluated using real-time PCR. The results further show that ECHDCl is significantly over-expressed in adipose tissues when compared to all other human adult tissues.

"Fold Change" indicates the fold expression calculated as the ratio of the mean adipose tissues expression/ mean other tissues expression. Numbers in parentheses indicates the number of human adult tissue samples analyzed by real-time PCR.

[282] ECHDCl contains the following protein domains (designated with reference to SEQ ID NO:29): Enoyl-CoA hydratase/isomerase family (PF00378) at amino acids 59 to 213. It is possible that ECHDCl has similar activity as to enoyl-CoA hydratase which catalyzes the second step in beta-oxidation of fatty acids.

ECHDC3

[283] Probe set 219298 detects ECHDC3 nucleic acid sequences. Expression of ECHDC3 transcripts was decreased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[284] ECHDC3 was also evaluated using real-time PCR. The results further show that ECHDC3 is significantly under-expressed in subcutaneous adipose from obese individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean obese expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR. [285] ECHDC3 contains the following protein domains (designated with reference to SEQ ID NO:39): Enoyl-CoA hydratase/isomerase family (PF00378) at amino acids 57 to 225. It is possible that ECHDC3 has similar activity as to enoyl-CoA hydratase which catalyzes the second step in beta-oxidation of fatty acids.

HADHSC

[286] Probe set 211569 detects HADHSC nucleic acid sequences. Expression of HADHSC transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[287] HADHSC was also evaluated using real-time PCR. The results further show that HADHSC is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[288] Probe set 211569 detects HADHSC nucleic acid sequences.

Expression of HADHSC transcripts was decreased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[289] HADHSC contains the following protein domains (designated with reference to SEQ ID NO:43): 3-hydroxyacyl-CoA dehydrogenase, NAD binding domain (PF02737) at amino acids 25 to 214; and 3-hydroxyacyl-CoA dehydrogenase, C-terminal domain (PF00725) at amino acids 216 to 313. HADHSC plays an essential role in the mitochondrial beta-oxidation of short chain fatty acids. It catalyzes the reversible dehydrogenation of 3-hydroxyacyl-CoAs to their corresponding 3-ketoacyl-CoAs with concomitant reduction of NAD to NADH and exerts it highest activity toward 3- hydroxybutyryl-CoA.

LGLL338

[290] Probe set 235496 detects LGLL338 nucleic acid sequences. Expression of LGLL338 transcripts was increased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[291] LGLL338 was also evaluated using real-time PCR. The results further show that LGLL338 is significantly over-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[292] Probe set 235496 detects LGLL338 nucleic acid sequences. Expression of LGLL338 transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[293] LGLL338 contains the following protein domains (designated with reference to SEQ ID NO:51): 1 transmembrane domain (TMHMM2.0) at amino acids 10 to 32.

MGC10946

[294] Probe set MBXHUMFAT06172 detects MGC10946 nucleic acid sequences. Expression of MGC 10946 transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients. [295] MGC 10946 was also evaluated using real-time PCR. The results further show that MGC 10946 is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[296] MGCl 0946 contains the following protein domains (designated with reference to SEQ ID NO:57): Signal peptide at amino acids 1 to 26; and 1 transmembrane domain (TMHMM2.0) at amino acids 4 to 26. A soluble active secreted form of MGC10946 has been predicted and this is displayed in SEQ ID NO:58.

NPRl

[297] Probe set 204648 detects NPRl nucleic acid sequences. Expression of NPRl transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[298] NPRl was also evaluated using real-time PCR. The results further show that NPRl is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[299] Probe set 204648 detects NPRl nucleic acid sequences. Expression of NPRl transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[300] NPRl was also evaluated using real-time PCR. The results further show that NPRl is significantly over-expressed in adipose tissues when compared to all other human adult tissues.

"Fold Change" indicates the fold expression calculated as the ratio of the mean adipose tissues expression/ mean other tissues expression. Numbers in parentheses indicates the number of human adult tissue samples analyzed by real-time PCR.

[301] NPRl contains the following protein domains (designated with reference to SEQ ID NO: 64): Receptor family ligand binding region (PFOl 094) at amino acids 54 to 417; Adenylate and Guanylate cyclase catalytic domain (PF00211) at amino acids 867 to 1053; and Protein kinase domain (PF00069) at amino acids 538 to 801. NPRl is a membrane-bound guanylate cyclase that serves as the receptor for both atrial and brain natriuretic peptides. Natriuretic peptide binding to NPRl activates the intrinsic guanylyl cyclase activity, resulting in a rapid increase in cytosolic cGMP that subsequently activates protein kinase G (Airhart, N. et al, J Biol Chem. 278:38693-8 (2003)). Atrial natriuretic peptide initiates natriuresis, diuresis, and vasodilation, all of which contribute to lowering blood pressure whereas the structurally related peptide, brain natriuretic peptide has similar effects but mainly functions in the cardiac ventricles.

PLD3

[302] Probe set 201050 detects PLD3 nucleic acid sequences. Expression of PLD3 transcripts was increased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[303] PLD3 was also evaluated using real-time PCR. The results further show that PLD3 is significantly over-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[304] PLD3 contains the following protein domains (designated with reference to SEQ ID NO:70): Phospholipase D. Active site motif (PF00614) at amino acids 143 to 170, 358 to 384. This domain is found in other enzymes which are members of the phospholipase superfamily of enzymes which are known to hydrolyze the terminal phosphodiester bond of phospholipids to phosphatidic acid. Phosphatidic acid is a lipid mediator involved in signal transduction. PTGER2

[305] Probe set 206631 detects PTGER2 nucleic acid sequences. Expression of PTGER2 transcripts was increased in rosi compared to vehicle treated cultures of primary human adipocytes in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Pre-Rosi" and "Post-Rosi" indicates sample was taken before or after 24 hours of rosiglitazone treatment; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of primary human adipocytes post-rosi in comparison to pre-rosi samples.

[306] PTGER2 was also evaluated using real-time PCR. The results further show that PTGER2 is significantly over-expressed in primary cultured human adipocytes treated with rosi when compared to vehicle.

"Fold Change" indicates the fold expression calculated as the ratio of the mean rosi expression/ mean vehicle expression. Numbers in parentheses indicates the number of primary human adipocyte samples analyzed by real-time PCR.

[307] PTGER2 was over-expressed in 3T3-L1 adipocytes and the effect on basal and insulin stimulated glucose transport and Glut 4 translocation was determined.

Glucose Transport Analysis in 3T3-L1 Adipocytes:

Legend: "Con" indicates control 3T3-L1 adipocytes that do not express hPTGER2. "FC" indicates the fold change defined as the following ratio; glucose transport in hPTGER2-expressing cells incubated for 3 hours with 1 uM butaprost free acid/glucose transport in non-PTGER2-expressing cells incubated for 3 hours with 1 uM butaprost free acid, h" is human, "n" is the number of experiments. SEM is the standard error of the mean.

[308] The results show that increasing the levels of PTGER2 in a cell such as an adipocyte treated with a PTGER2 ligand leads to a corresponding increase in glucose uptake. This indicates that increasing the levels or activity of PTGER2 in tissues of insulin resistant patients or diabetic patients will increase the ability of such tissues to take up glucose and hence, will provide an effective treatment for insulin resistance and diabetes. [309] PTGER2 contains the following protein domains (designated with reference to SEQ ID NO:78): 7 transmembrane receptor (rhodopsin family) (PFOOOOl) at amino acids 38 to 315. Mice deficient in the PTGER2 displayed resting systolic blood pressure that was significantly lower than that in wildtype controls. The blood pressure was found to increase in these animals when they were placed on a high salt diet, suggesting that the EP2 receptor may be involved in sodium handling by the kidney (Tilley, S. L. et al, J. Clin. Invest. 103: 1539-1545 (1999)).

[310] PTGER2 is a G protein coupled receptor, activation of which increases intracellular cyclic AMP {see, e.g., Bastien, et al., J. Biol.Chem 269:11873-11877 (1994), Katsuyama, et al. FEBS Lett. 372:151-156 (1995)). Agonists of PTGER2 can therefore be identified, e.g., by screening cells with high levels of PTGER2. to identify compounds that increase intracellular cyclic AMP.

[311] A number of PTGER2 selective agonists have been described. In addition to prostaglandin E2 itself, these include, for example, prostaglandin El; butaprost free acid (GR32191B, 9-oxo -1 lα, lόR-dihdroxy-π-cyclobutyl-prost-lSE-en-l-oic acid), Regan, et al. MoI Pharmacol. 46:213-220 (1994); 16,16, dimethyl prostaglandin E2, Wilson, et al. Eur. J. Pharmacol 501:49-58 (2004); misoprostol (9-oxo -l lα, 16-dihdroxy-16-methyl- prost-13E-en-l-oic acid, methyl ester), Colman et al. Pharmacol. Rev. 46:205-229 (1994); CP-533,536 (3-{[4-tert-butyl-benzyl),-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid (Li et al. J. Bone Miner. Res 18:2033-2042 (2003)); structural hybrids of butaprost and PGE2, Tani. et al Bioorg. Med. Chem Lett 11:2025-2028 (2001); and 16-hydroxy-17,17- trimethylene PGE2 derivatives, Tani et al Bioorg Med. Chem 10:1093-1106 (2002). These, or other PTGER2 agonists, are useful in the treatment of insulin resistance and Type II diabetes. PTGER3

[312] Probe set 210374 detects PTGER3 nucleic acid sequences. Expression of PTGER3 transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[313] PTGER3 was also evaluated using real-time PCR. The results further show that PTGER3 is significantly over-expressed in adipose tissues when compared to all other human adult tissues.

"Fold Change" indicates the fold expression calculated as the ratio of the mean adipose tissues expression/ mean other tissues expression. Numbers in parentheses indicates the number of human adult tissue samples analyzed by real-time PCR.

[314] PTGER3 was over-expressed in 3T3-L1 adipocytes and the effect on basal and insulin stimulated glucose transport and Glut 4 translocation was determined.

Glucose Transport Analysis in 3T3-L1 Adipocytes:

Legend: "Con" indicates control 3T3-L1 adipocytes that do not express hPTGER3. "FC" indicates the fold change defined as the following ratio; glucose transport in hPTGER3-expressing cells incubated for 1 hour with 1 uM sulprostone /glucose transport in non-PTGER3 -expressing cells incubated for 1 hour with 1 uM sulprostone. h" is human, "n" is the number of experiments. SEM is the standard error of the mean.

[315] The results show that increasing the levels of PTGER3 in a cell such as an adipocyte treated with a PTGER3 ligand leads to a corresponding increase in glucose uptake. This indicates that increasing the levels or activity of PTGER3 in tissues of insulin resistant patients or diabetic patients will increase the ability of such tissues to take up glucose and hence, will provide an effective treatment for insulin resistance and diabetes. [316] PTGER3 contains the following protein domains (designated with reference to SEQ ID NO:84): 7 transmembrane receptor (rhodopsin family) (PFOOOOl) at amino acids 65 to 346. This receptor may have many biological functions, which involve digestion, nervous system, kidney reabsorption, and uterine contraction activities. Studies in the mouse suggest that this receptor may also mediate adrenocorticotropic hormone response as well as fever generation in response to exogenous and endogenous stimuli (Matsuoka, Y., et al Proc Natl Acad Sd USA 100, 4132-4137 (2003)). Multiple alternatively spliced transcript variants encoding eight distinct isoforms have been reported.

[317] The PTGER3 receptor is a G protein coupled receptor linked to the inhibition of adenylate cyclase (see, e.g., Kunapuli, et al. Biochem. J. 298:263-267 (1994)). Agonists of the PTGER3 receptor can therefore be identified, e.g., by screening cells with high levels of the PTGER3 receptor and treated with forskolin to identify compounds that decrease the levels of cyclic AMP.

[318] A number of PTRGE3 selective agonists have been described. In addition to prostaglandin E2 itself, these include Sulprostone (N-(methylsulphonyl)-9-oxo- l lα, 15R-dihydroxy-16-phenoxy-17, 18, 19, 20-tetranor-prosta-5Z, 13E-dien-l-amide) (CP- 34089/ZK-57671), Schaaf,. et al. J. Med, Chem. 24:1353-1359 (1981); MB28767 (+/- 11- deoxy-16-ρhenoxy-omega-tetranor PGEl), Banerjee, et al Life ScL 35:2489-2496 (1984) and Sugimoto, et al, J. Biol. Chem 267:6463-6466 (1992); TEI 3356 (15-deoxy-16-methyl- isocarbacyclin), Negishi, et al, Prostaglandins 48:275-283 (1994); 2-(arylmethyl) cinnamic acid derivatives, Juteau, et al, Bioorg. Med Chem. Lett 11 :747-749 (2001); GR 63799X (IR- [lα(Z),2β(R*), 3α]-(-)-4-benzoylamino) phenyl-7-[3-hydroxy-3-phenoxy-propoxy)-5- oxocyclopentyl]-4-heptenoate), Bunce, et al.,, Adv Prostaglandin Thromboxane Leukot Res. 21A:379-382.(1991); 13.14-Didehydro-16-phenoxy PGEl analogues, Shimazaki,. et al Bioorg. Med. Chem. 8:353-362 (2000); SC-46275, Savage, et al, Prostaglandins Leukot Essent Fatty Acids 49:939-943 (1993); and 16,16-dimethyl PGE2 and 11-deoxyPGEl. Narumiya et al. Physiol. Rev 79: 1193-1226 (1999). These and other PTGER3 agonists agonists are useful in the treatment of insulin resistance and Type II diabetes

PTGER4

[319] Probe set 204897 detects PTGER4 nucleic acid sequences. Expression of PTGER4 transcripts was decreased in pio compared to vehicle treated cultures of primary human adipocytes in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Pre-Pio" and "Post-Pio" indicates sample was taken before or after 24 hours of pioglitazone treatment; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of primary human adipocytes post-pio in comparison to pre-pio samples.

[320] PTGER4 was also evaluated using real-time PCR. The results further show that PTGER4 is significantly under-expressed in primary cultured human adipocytes treated with pio when compared to vehicle.

"Fold Change" indicates the fold expression calculated as the ratio of the mean pio expression/ mean vehicle expression. Numbers in parentheses indicates the number of primary human adipocyte samples analyzed by real-time PCR.

[321] Probe set 204897 detects PTGER4 nucleic acid sequences. Expression of PTGER4 transcripts was decreased in rosi compared to vehicle treated cultures of primary human adipocytes in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Pre-Rosi" and "Post-Rosi" indicates sample was taken before or after 24 hours of rosiglitazone treatment; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of primary human adipocytes post-rosi in comparison to pre-rosi samples.

[322] PTGER4 was also evaluated using real-time PCR. The results further show that PTGER4 is significantly under-expressed in primary cultured human adipocytes treated with rosi when compared to vehicle.

"Fold Change" indicates the fold expression calculated as the ratio of the mean rosi expression/ mean vehicle expression. Numbers in parentheses indicates the number of primary human adipocyte samples analyzed by real-time PCR.

[323] PTGER4 contains the following protein domains (designated with reference to SEQ ID NO:90): C.elegans Srg family integral membrane protein (PF02118) at amino acids 1 to 293; 7TM chemoreceptor (PFOl 604) at amino acids 19 to 299; and 7 transmembrane receptor (rhodopsin family) (PFOOOOl) at amino acids 34 to 329. This receptor can activate T-cell factor signaling. It has been shown to mediate PGE2 induced expression of early growth response 1 (EGRl), regulate the level and stability of cyclooxygenase-2 mRNA, and lead to the phosphorylation of glycogen synthase kinase-3. Knockout studies in mice suggest that this receptor may be involved in the neonatal adaptation of circulatory system, osteoporosis, as well as initiation of skin immune responses.

RARRES2

[324] Probe set 209496 detects RARRES2 nucleic acid sequences. Expression of RARRES2 transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[325] RARRES2 was also evaluated using real-time PCR. The results further show that RARRES2 is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[326] Probe set 209496 detects RARRES2 nucleic acid sequences.

Expression of RARRES2 transcripts was decreased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[327] RARRES2 was also evaluated using real-time PCR. The results further show that RARRES2 is significantly under-expressed in subcutaneous adipose from obese individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean obese expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[328] Probe set 209496 detects RARRES2 nucleic acid sequences. Expression of RARRES2 transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[329] RARRES2 was also evaluated using real-time PCR. The results further show that RARRES2 is significantly over-expressed in adipose tissues when compared to all other human adult tissues.

"Fold Change" indicates the fold expression calculated as the ratio of the mean adipose tissues expression/ mean other tissues expression. Numbers in parentheses indicates the number of human adult tissue samples analyzed by real-time PCR.

[330] RARRES2 contains the following protein domains (designated with reference to SEQ ID NO:96): Signal peptide at amino acids 1 to 20. A soluble active secreted form of RARRES2 has been detected (Meder, W. et al, FEBS Lett. 2003 Dec 18;555(3):495- 9) and this is displayed in SEQ ID NO:97. RARRES2 is the ligand for ChemR23. ChemR23 is a putative chemoattractant receptor relatively specific for antigen-presenting cells and it could play an important role in the recruitment or trafficking of these cell populations (Samson, M. et al, Eur J Immunol. 28:1689-7000 (1998); Wittamer, V., et al, J Exp Med. 198(7):977-85 (2003)).

SCRN2

[331] Probe set 228730 detects SCRN2 nucleic acid sequences. Expression of SCRN2 transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[332] SCRN2 was also evaluated using real-time PCR. The results further show that SCRN2 is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[333] Probe set 228730 detects SCRN2 nucleic acid sequences. Expression of SCRN2 transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[334] SCRN2 was also evaluated using real-time PCR. The results further show that SCRN2 is significantly over-expressed in adipose tissues when compared to all other human adult tissues.

"Fold Change" indicates the fold expression calculated as the ratio of the mean adipose tissues expression/ mean other tissues expression. Numbers in parentheses indicates the number of human adult tissue samples analyzed by real-time PCR.

[335] SCRN2 contains the following protein domains (designated with reference to SEQ ID NO:103): Peptidase family U34 (PF03577) at amino acids 11 to 370.

TLR8

[336] Probe set 229560 detects TLR8 nucleic acid sequences. Expression of TLR8 transcripts was increased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients. [337] TLR8 was also evaluated using real-time PCR. The results further show that TLR8 is significantly over-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[338] TLR8 contains the following protein domains (designated with reference to SEQ ID NO:109): TIR domain (PF01582) at amino acids 900 to 1039; Leucine Rich Repeat (PF00560) at amino acids 82 to 105, 106 to 143, 241 to 264, 265 to 305, 306 to 329, 330 to 354, 658 to 681, 731 to 754; and 1 transmembrane domain (TMHMM2.0) at amino acids 844 to 866. TLR8 is thought to recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents and mediate the production of cytokines necessary for the development of an effective immune response.

TM7SF2

[339] Probe set 210130 detects TM7SF2 nucleic acid sequences. Expression of TM7SF2 transcripts was decreased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[340] TM7SF2 was also evaluated using real-time PCR. The results further show that TM7SF2 is significantly under-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[341] Probe set 210130 detects TM7SF2 nucleic acid sequences. Expression of TM7SF2 transcripts was decreased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[342] Probe set 210130 detects TM7SF2 nucleic acid sequences. Expression of TM7SF2 transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[343] TM7SF2 contains the following protein domains (designated with reference to SEQ ID NO:115): Protein of unknown function (DUF1295) (PF06966) at amino acids 200 to 409; Ergosterol biosynthesis ERG4/ERG24 family (PFO 1222) at amino acids 7 to 418; and 7 transmembrane domains (TMHMM2.0) at amino acids 13 to 35, 62 to 81, 102 to 124, 129 to 148, 255 to 277, 287 to 304, 355 to 377. The transmembrane region shares 59% identity with the transmembrane region of the lamin B receptor and 38 to 46% identity with the transmembrane regions of the C14 sterol reductases from different species. This suggests TM7SF2 may play a role in sterol metabolism.

TNMD

[344] Probe set 220065 detects TNMD nucleic acid sequences. Expression of

TNMD transcripts was increased in diabetic compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of diabetics in comparison to lean patients.

[345] TNMD was also evaluated using real-time PCR. The results further show that TNMD is significantly over-expressed in subcutaneous adipose from diabetic individuals when compared to subcutaneous adipose from lean individuals.

"Fold Change" indicates the fold expression calculated as the ratio of the mean diabetic expression/ mean lean expression. Numbers in parentheses indicates the number of patient samples analyzed by real-time PCR.

[346] Probe set 220065 detects TNMD nucleic acid sequences. Expression of TNMD transcripts was increased in obese compared to lean patients in the gene profiling experiment.

B/C indicates sample is from Basal or Clamp; "Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of patient samples; "Fold Change" indicates fold change of obese in comparison to lean patients.

[347] Probe set 220065 detects TNMD nucleic acid sequences. Expression of TNMD transcripts was increased in adipose tissues compared to all other human adult tissues in the gene profiling experiment.

"Mean Expr" indicates mean expression; "SEM" indicates standard error of mean; "n" indicates number of tissue samples; "Fold Change" indicates fold change of adipose tissues in comparison to all other human adult tissues profiled.

[348] TNMD contains the following protein domains (designated with reference to SEQ ID NO: 125): BRICHOS domain (PF04089) at amino acids 93 to 186; and 1 transmembrane domain (TMHMM2.0) at amino acids 31 to 50. TNMD may function as a type II transmembrane protein on cell surface (Shukunami, C. et ah, Biochem Biophys Res Commun. 280:1323-7 (2001)).

SEQ ID NO: 1

gi|17196625|ref]NM_025225.2| Homo sapiens chromosome 22 open reading frame 20 (C22or£20), mRNA i atggtccgag gggggcgggg ctgacgtcgc gctgggaatg ccctggccga gacactgagg

61 cagggtagag agcgcttgcg ggcgccgggc ggagctgctg cggatcagga cccgagccga

121 ttcccgatcc cgacccagat cctaacccgc gcccccgccc cgccgccgcc gccatgtacg

181 acgcagagcg cggctggagc ttgtccttcg cgggctgcgg cttcctgggc ttctaccacg

241 tcggggcgac ccgctgcctg agcgagcacg ccccgcacct cctccgcgac gcgcgcatgt

301 tgttcggcgc ttcggccggg gcgttgcact gcgtcggcgt cctctccggt atcccgctgg

361 agcagactct gcaggtcctc tcagatcttg tgcggaaggc caggagtcgg aacattggca

421 tcttccatcc atccttcaac ttaagcaagt tcctccgaca gggtctctgc aaatgcctcc

481 cggccaatgt ccaccagctc atctccggca aaataggcat ctctcttacc agagtgtctg

541 atggggaaaa cgttctggtg tctgactttc ggtccaaaga cgaagtcgtg gatgccttgg

601 tatgttcctg cttcatcccc ttctacagtg gccttatccc tccttccttc agaggcgtgc

661 gatatgtgga tggaggagtg agtgacaacg tacccttcat tgatgccaaa acaaccatca

721 ccgtgtcccc cttctatggg gagtacgaca tctgccctaa agtcaagtcc acgaactttc

781 ttcatgtgga catcaccaag ctcagtctac gcctctgcac agggaacctc taccttctct

841 cgagagcttt tgtccccccg gatctcaagg tgctgggaga gatatgcctt cgaggatatt

901 tggatgcatt caggttcttg gaagagaagg gcatctgcaa caggccccag ccaggcctga

961 agtcatcctc agaagggatg gatcctgagg tcgccatgcc cagctgggca aacatgagtc

1021 tggattcttc cccggagtcg gctgccttgg ctgtgaggct ggagggagat gagctgctag

1081 accacctgcg tctcagcatc ctgccctggg atgagagcat cctggacacc ctctcgccca

1141 ggctcgctac agcactgagt gaagaaatga aagacaaagg tggatacatg agcaagattt

1201 gcaacttgct acccattagg ataatgtctt atgtaatgct gccctgtacc ctgcctgtgg

1261 aatctgccat tgcgattgtc cagagactgg tgacatggct tccagatatg cccgacgatg

1321 tcctgtggtt gcagtgggtg acctcacagg tgttcactcg agtgctgatg tgtctgctcc

1381 ccgcctccag gtcccaaatg ccagtgagca gccaacaggc ctccccatgc acacctgagc

1441 aggactggcc ctgctggact ccctgctccc ccaagggctg tccagcagag accaaagcag

1501 aggccacccc gcggtccatc ctcaggtcca gcctgaactt cttcttgggc aataaagtac

1561 ctgctggtgc tgaggggctc tccacctttc ccagtttttc actagagaag agtctgtgag

1621 tcacttgagg aggcgagtct agcagattct ttcagaggtg ctaaagtttc ccatctttgt

1681 gcagctacct ccgcattgct gtgtagtgac ccctgcctgt gacgtggagg atcccagcct

1741 ctgagctgag ttggttttat gaaaagctag gaagcaacct ttcgcctgtg cagcggtcca

1801 gcacttaact ctaatacatc agcatgcgtt aattcagctg gttgggaaat gacaccagga

1861 agcccagtgc agagggtccc ttactgactg tttcgtggcc ctattaatgg tcagactgtt

1921 ccagcatgag gttcttagaa tgacaggtgt ttggatgggt gggggccttg tgatgggggg

1981 taggctggcc catgtgtgat cttgtggggt ggagggaaga gaatagcatg atcccacttc

2041 cccatgctgt gggaaggggt gcagttcgtc cccaagaacg acactgcctg tcaggtggtc

2101 tgcaaagatg ataaccttga ctactaaaaa cgtctccatg gcgggggtaa caagatgata

2161 atctacttaa ttttagaaca cctttttcac ctaactaaaa taatgtttaa agagttttgt

2221 ataaaaatgt aaggaagcgt tgttacctgt tgaattttgt attatgtgaa tcagtgagat

2281 gttagtagaa taagccttaa aaaaaaaaaa atcggttggg tgcagtggca cacggctgta

2341 atcccagcac tttgggaggc caaggttggc agatcacctg aggtcaggag ttcaagacca

2401 gtctggccaa catagcaaaa ccctgtctct actaaaaata caaaaattat ctgggcatgg

2461 tggtgcatgc ctgtaatccc agctattcgg aaggctgagg caggagaatc acttgaaccc

2521 aggaggcgga ggttgcggtg agctgagatt gcaccatttc attccagcct gggcaacatg

2581 agtgaaagtc tgactcaaaa aaaaaaaatt taaaaaacaa aataatctag tgtgcagggc

2641 attcacctca gccccccagg caggagccaa gcacagcagg agcttccgcc tcctctccac

2701 tggagcacac aacttgaacc tggcttattt tctgcaggga ccagccccac atggtcagtg

2761 agtttctccc catgtgtggc gatgagagag tgtagaaata aagac

SEQ ID NO: 2

Amino acid sequence of human ADPN encoded by the DNA sequence shown in SEQ ID NO: 1. MYDAERGWSLSFAGCGFLGFYHVGATRCLSEHAPHLLRDARMLFGASAGALHCVGVLSGI PLEQTLQVLSDLVRKARSRNIGIFHPSFNLSKFLRQGLCKCLPANVHQLISGKIGISLTR VSDGENVLVSDFRSKDEVVDALVCSCFIPFYSGLIPPSFRGVRYVDGGVSDNVPFIDAKT TITVSPFYGEYDICPKVKSTNFLHVDITKLSLRLCTGNLYLLSRAFVPPDLKVLGEICLR GYLDAFRFLEEKGICNRPQPGLKSSSEGMDPEVAMPSWANMSLDSSPESAALAVRLEGDE LLDHLRLSILPWDESILDTLSPRLATALSEEMKDKGGYMSKICNLLPIRIMSYVMLPCTL PVESAIAIVQRLVTWLPDMPDDVLWLQWVTSQVFTRVLMCLLPASRSQMPVSSQQASPCT PEQDWPCWTPCSPKGCPAETKAEATPRSILRSSLNFFLGNKVPAGAEGLSTFPSFSLEKS L SEQ ID NO: 3 gi|16905118|reflNM_054088.1| Mus musculus adiponutrin (Adpn), mRNA i ggagctgaac tgcagcgccg cccggagctt caagcaccat gtatgaccca gagcgccgct

61 ggagcctgtc gtttgcaggc tgcggcttcc tgggcttcta ccacgtcggg gctacgctat

121 gtctgagcga gcgcgccccg cacctcctcc gcgatgcgcg cactttcttt ggctgctcgg

181 ccggtgcact gcacgcggtc accttcgtgt gcagtctccc tctcggccgt ataatggaga

241 tcctcatgga cctcgtgcgg aaagccagga gccgcaacat cggcaccctc cacccgttct

301 tcaacattaa caagtgcatc agagacgggc tccaggagag cctcccagac aatgtccacc

361 aggtcatttc tggcaaggtt cacatctcac tcaccagggt gtcggatggg gagaacgtgc

421 tggtgtctga gttccattcc aaagacgaag tcgtggatgc cctggtgtgt tcctgcttca

481 ttcccctctt ctctggccta atccctcctt ccttccgagg cgagcggtac gtggacggag

541 gagtgagcga caacgtccct gtgctggatg ccaaaaccac catcacggtg tcacctttct

601 acggtgagca tgacatctgc cccaaagtca agtccaccaa cttcttccac gtgaatatca

661 ccaacctcag cctccgcctc tgcactggga acctccaact tctgaccaga gcgctcttcc

721 cgtctgatgt gaaggtgatg ggagagctgt gctatcaagg gtacctggac gccttccggt

781 tcctggagga gaatggcatc tgtaacgggc cacagcgcag cctgagtctg tccttggtgg

841 cgccagaagc ctgcttggaa aatggcaaac ttgtgggaga caaggtgcca gtcagcctat

901 gctttacaga tgagaacatc tgggagacac tgtcccccga gctcagcaca gctctgagtg

961 aagcgattaa ggacagggag ggctacctga gcaaagtctg caacctcctg cccgtcagga

1021 tcctgtccta catcatgctg ccctgcagtc tgcccgtgga gtcggctatc gctgcagtcc

1081 acaggctggt gacatggctc cctgatatcc aggatgatat ccagtggcta caatgggcga

1141 catcccaggt ttgtgcccga atgacgatgt gcctgctccc ctctaccaga tcccgagcat

1201 ccaaggatga ccatcgaatg ctcaagcatg gccatcaccc atctccccac aagcctcaag

1261 gcaactctgc tggtttgtaa attgctggtc tccgtgcttc cagtgaactt ggacattctt

1321 ctcatggttg gtccaggaga ggccaaagct gagggcaccc tgccttccac ccccagtcca

1381 gcttgacctt ttatctggag caacagtgtc tagatgatgg gtgggtgagg ggtgctatac

1441 tgtctgtccc tctgggaagg gttctgttac ttttggaggc agctaggaag tttctctgtg

1501 cagctgcccc ctggtgctgt gtggtgacct cattgcctgt gaccccagga tcacaggatc

1561 tgggctaaag tggtagtcca tagaaaccaa agacaatgat ttggtgttta gaaagctact

1621 cttggtctgg gtgaagtctg gtgcttaagg gctatcacaa agagcgtgtc aaaccatctc

1681 tcagcctgtg agtcagtggg gagcccaagg gcatcagtgt ttggaaactg gaatccaaac

1741 cgggcaatct cggaaggaaa ctgtttagga attgtgatgg gacgggccgt ggctgtctct

1801 gaaaagggcc tgccagataa cttattactt ttaaggacac ctttggctct tactacttta

1861 taaagcattt tatataaaca caccagggag tgcatggtga actacacgta tgatcagtta

1921 agtggggcta gaattaggta gggagagcat cggacctctg cctcctcaac ctcaacttgc

1981 ttgctttctc cactggctcc aaatctttgt atagtcatca gccatgacca cctctctccc

2041 tccccatcta ctaccagcag cgttaatggg aataagtacc cacttctctc aggtgtacta

2101 tacagctgtg ggtgtggtgt gtgtttcctg taattcacac tttagaaagg aaacaagcaa

2161 acaaaagaaa ccaggtgctg cccatagtcc taagtgtaga cagtgaaggt gtgtgtctcc

2221 catgcctgag tctcctggag gcctagtgag ctccaggttc atgcaagcac atcaggagga

2281 atcatataat ctcagcacgg ttgatccaga tgggataaga aaggactctc ggagagagaa

2341 tgtggttcta gagacaaagt gtctaggcta cacagaagat aagactgtcc caaggaaaga

2401 aaagaaacca ggaactaggg tgcagctcag ttgtcagagg aattctctag gcttgaagcc

2461 cagagtccaa tctcagcacc ttataaactg tggagtgaca ggcagtgaca tcggcctgta

2521 atcccaacac tcaagcagta gaggcaagag gatcataagt tcaaggtctt ccttggctat

2581 ttagggagtt ggaggttagc tctggctaca tgagaccctg tctcaaaaaa aaaaaaaaaa

2641 aaaaagtaga aacttctgcc ttgctttgag ctgccccttt ctggacgttt ctcatcagta

2701 gagaatattc ctgccaccct atcagacaaa actcccactg gtttggagtc tctccattct 2761 caggaacacc tcaggagtca gacagtgagc agcagggagc aattttttga cttgtaagcc

2821 ccttaccaag cctggttcat ttgtttatta aaagcaggtg tgggtgaatt tatgcaaatg

2881 agtatgcaaa ctagtggaac agcagaagga ttgaatggat acaccaaaaa taaccacaac

2941 tgtttaaggg aaaagggtcc ataataaatg tggggaacaa aaaacaaata aatgtgattt 3001 tttttag

SEQ ID NO: 4

Amino acid sequence of mouse ADPN encoded by the DNA sequence shown in SEQ ID NO: 3.

MYDPERRWSLSFAGCGFLGFYHVGATLCLSERAPHLLRDARTFFGCSAGALHAVTFVCSL PLGRIMEILMDLVRKARSRNIGTLHPFFNINKCIRDGLQESLPDNVHQVISGKVHISLTR

VSDGENVLVSEFHSKDEVVDALVCSCFIPLFSGLIPPSFRGERYVDGGVSDNVPVLDAKT

TITVSPFYGEHDICPKVKSTNFFHVNITNLSLRLCTGNLQLLTRALFPSDVKVMGELCYQ

GYLDAFRFLEENGICNGPQRSLSLSLVAPEACLENGKLVGDKVPVSLCFTDENIWETLSP

ELSTALSEAIKDREGYLSKVCNLLPVRILSYIMLPCSLPVESAIAAVHRLVTWLPDIQDD IQWLQWATSQVCARMTMCLLPSTRSRASKDDHRMLKHGHHPSPHKPQGNSAGL

SEQIDNO: 5

ENSRNOT00000015767cDNAsequence,EnsEMBLtranscript[Rattusnorvegicus]

1 atgtacgacc cagagcgccg ctggagcctg tcgttcgcag gctgcggctt cctaggcttc

61 taccacatcg gggctacgct atgtctgagc gagcgcgctc cgcacatcct ccgcgaagcg 121 cgcactttct tcggctgctc ggccggtgca ctgcacgcgg tcaccttcgt gtgcagtctc

181 cctctcgatc acatcatgga gatcctcatg gacctcgtgc ggaaagccag gagccgcaac

241 atcggcaccc tccacccgtt cttcaacatt aacaagtgcg tcagagacgg ccttcaggag

301 accctcccag acaacgtcca ccagatcatt tctggcaagg tttacatctc actcaccaga

361 gtgtccgatg gggagaacgt gctggtgtct gagttccatt ccaaagacga agtggtggat 421 gccctggtgt gctcctgctt cattcctctc ttctctggcc taatccctcc ttccttccga

481 gtaccctccc tttccccttc cttacagcgg tacgtggatg gaggagtgag tgacaacgtc

541 cctgtgctgg acgccaaaac caccatcacg gtgtcccctt tctatggtga gcatgacatc

601 tgtcccaaag tgaagtccac caacttcctc caggtgaata tcaccaacct cagtcttcgt

661 ctctgcactg ggaaccttca tcttctgacc agagcactct tcccatctga tgtgaaggtg 721 atgggagagc tgtgctttca agggtacctg gacgccttcc ggttcctgga agagaacggc

781 atctgtaatg ggccacagcg cagcctgagt ctgtccttgg agaaggaaat ggcgccagaa

841 accatgatac cctgcttgga aaatggccac cttgtagcag ggaacaaggt gccagtaagc

901 tgtgtatgcc ttacagctgt gccgtcggat gagagcatct gggagatgct gtcccccaag

961 ctcagcacag ctctgactga agcgattaaa gacagggggg gctacctgaa caaagtctgc 1021 aacctcctgc ccattaggat cctgtcctac atcttgctgc cctgcactct gcccgtggag

1081 tcggccatcg ctgcagtcca caggctggtg atgtggctcc ctgatatcca tgaagatatc

1141 cagtggctac agtgggcaac atcccaggtg tgtgcccgaa tgaccatgtg cctgctcccc

1201 tctaccagat ccagagcatc caaggataac catcaaacac tcaagcatgg atatcaccca

1261 tctctccaca aaccccaagg cagctctgcc ggtttgtaa SEQIDNO: 6

Amino acid sequence of rat ADPN encoded by the DNA sequence shown in SEQ ID NO: 5.

MYDPERRWSLSFAGCGFLGFYHIGATLCLSERAPHILREARTFFGCSAGALHAVTFVCSL PLDHIMEILMDLVRKARSRNIGTLHPFFNINKCVRDGLQETLPDNVHQIISGKVYISLTR VSDGENVLVSEFHSKDEVVDALVCSCFIPLFSGLIPPSFRVPSLSPSLQRYVDGGVSDNV PVLDAKTTITVSPFYGEHDICPKVKSTNFLQVNITNLSLRLCTGNLHLLTRALFPSDVKV MGELCFQGYLDAFRFLEENGICNGPQRSLSLSLEKEMAPETMIPCLENGHLVAGNKVPVS CVCLTAVPSDESIWEMLSPKLSTALTEAIKDRGGYLNKVCNLLPIRILSYILLPCTLPVE SAIAAVHRLVMWLPDIHEDIQWLQWATSQVCARMTMCLLPSTRSRASKDNHQTLKHGYHP SLHKPQGSSAGL

SEQ ID NO: 7 gi|4502056|re^NM_000698.1| Homo sapiens arachidonate 5-lipoxygenase (ALOX5), mRNA i gggcgccgag gctccccgcc gctcgctgct ccccggcccg cgccatgccc tcctacacgg

61 tcaccgtggc cactggcagc cagtggttcg ccggcactga cgactacatc tacctcagcc

121 tcgtgggctc ggcgggctgc agcgagaagc acctgctgga caagcccttc tacaacgact

181 tcgagcgtgg cgcggtggat tcatacgacg tgactgtgga cgaggaactg ggcgagatcc

241 agctggtcag aatcgagaag cgcaagtact ggctgaatga cgactggtac ctgaagtaca

301 tcacgctgaa gacgccccac ggggactaca tcgagttccc ctgctaccgc tggatcaccg

361 gcgatgtcga ggttgtcctg agggatggac gcgcaaagtt ggcccgagat gaccaaattc

421 acattctcaa gcaacaccga cgtaaagaac tggaaacacg gcaaaaacaa tatcgatgga

481 tggagtggaa ccctggcttc cccttgagca tcgatgccaa atgccacaag gatttacccc

541 gtgatatcca gtttgatagt gaaaaaggag tggactttgt tctgaattac tccaaagcga

601 tggagaacct gttcatcaac cgcttcatgc acatgttcca gtcttcttgg aatgacttcg

661 ccgactttga gaaaatcttt gtcaagatca gcaacactat ttctgagcgg gtcatgaatc

721 actggcagga agacctgatg tttggctacc agttcctgaa tggctgcaac cctgtgttga

781 tccggcgctg cacagagctg cccgagaagc tcccggtgac cacggagatg gtagagtgca

841 gcctggagcg gcagctcagc ttggagcagg aggtccagca agggaacatt ttcatcgtgg

901 actttgagct gctggatggc atcgatgcca acaaaacaga cccctgcaca ctccagttcc

961 tggccgctcc catctgcttg ctgtataaga acctggccaa caagattgtc cccattgcca

1021 tccagctcaa ccaaatcccg ggagatgaga accctatttt cctcccttcg gatgcaaaat

1081 acgactggct tttggccaaa atctgggtgc gttccagtga cttccacgtc caccagacca

1141 tcacccacct tctgcgaaca catctggtgt ctgaggtttt tggcattgca atgtaccgcc

1201 agctgcctgc tgtgcacccc attttcaagc tgctggtggc acacgtgaga ttcaccattg

1261 caatcaacac caaggcccgt gagcagctca tctgcgagtg tggcctcttt gacaaggcca

1321 acgccacagg gggcggtggg cacgtgcaga tggtgcagag ggccatgaag gacctgacct

1381 atgcctccct gtgctttccc gaggccatca aggcccgggg catggagagc aaagaagaca

1441 tcccctacta cttctaccgg gacgacgggc tcctggtgtg ggaagccatc aggacgttca

1501 cggccgaggt ggtagacatc tactacgagg gcgaccaggt ggtggaggag gacccggagc

1561 tgcaggactt cgtgaacgat gtctacgtgt acggcatgcg gggccgcaag tcctcaggct

1621 tccccaagtc ggtcaagagc cgggagcagc tgtcggagta cctgaccgtg gtgatcttca

1681 ccgcctccgc ccagcacgcc gcggtcaact tcggccagta cgactggtgc tcctggatcc

1741 ccaatgcgcc cccaaccatg cgagccccgc caccgactgc caagggcgtg gtgaccattg

1801 agcagatcgt ggacacgctg cccgaccgcg gccgctcctg ctggcatctg ggtgcagtgt

1861 gggcgctgag ccagttccag gaaaacgagc tgttcctggg catgtaccca gaagagcatt

1921 ttatcgagaa gcctgtgaag gaagccatgg cccgattccg caagaacctc gaggccattg

1981 tcagcgtgat tgctgagcgc aacaagaaga agcagctgcc atattactac ttgtccccag

2041 accggattcc gaacagtgtg gccatctgag cacactgcca gtctcactgt gggaaggcca

2101 gctgccccag ccagatggac tccagcctgc ctggcaggct gtctggccag gcctcttggc

2161 agtcacatct cttcctccga ggccagtacc tttccattta ttctttgatc ttcagggaac

2221 tgcatagatt gtatcaaagt gtaaacacca tagggaccca ttctacacag agcaggactg

2281 cacaggcgtc ctgtccacac ccagctcagc atttccacac caagcagcaa cagcaaatca

2341 cgaccactga tagatgtcta ttcttgttgg agacatggga tgattatttt ctgttctatt

2401 tgtgcttagt ccaattcctt gcacatagta ggtacccaat tcaattacta ttgaatgaat

2461 taagaattgg ttgccataaa aataaatcag ttcattt

SEQIDNO:8

Amino acid sequence of human ALOX5 encoded by the DNA sequence shown in SEQ ID NO: 7.

MPSYTVTVATGSQWFAGTDDYIYLSLVGSAGCSEKHLLDKPFYNDFERGAVDSYDVTVDE ELGEIQLVRIEKRKYWLNDDWYLKYITLKTPHGDYIEFPCYRWITGDVEVVLRDGRAKLA RDDQIHILKQHRRKELETRQKQYRWMEWNPGFPLSIDAKCHKDLPRDIQFDSEKGVDFVL NYSKAMENLFINRFMHMFQSSWNDFADFEKIFVKISNTISERVMNHWQEDLMFGYQFLNG CNPVLIRRCTELPEKLPVTTEMVECSLERQLSLEQEVQQGNIFIVDFELLDGIDANKTDP CTLQFLAAPICLLYKNLANKIVPIAIQLNQIPGDENPIFLPSDAKYDWLLAKIWVRSSDF HVHQTITHLLRTHLVSEVFGIAMYRQLPAVHPIFKLLVAHVRFTIAINTKAREQLICECG LFDKANATGGGGHVQMVQRAMKDLTYASLCFPEAIKARGMESKEDIPYYFYRDDGLLAmE AIRTFTAEWDIYYEGDQWEEDPELQDFVNDVYVYGMRGRKSSGFPKSVKSREQLSEYL TWIFTASAQHAAVNFGQYDWCSWIPNAPPTMRAPPPTAKGWTIEQIVDTLPDRGRSCW HLGAVWALSQFQENELFLGMYPEEHFIEKPVKEAMARFRKNLEAIVSVIAERNKKKQLPY YYLSPDRI PNSVAI

SEQ ID NO: 9 gi|38085002|ref]XM_l 32832.31 Mus musculus hypothetical protein F730011J02 (F730011J02), mRNA i atgccctcct acacggtcac cgtggccacc ggcagccagt ggttcgcggg caccgacgac

61 tacatctacc tcagcctcat tggctctgcg ggctgtagcg agaagcatct gctggacaag

121 gcattctaca atgacttcga acggggcgcg gtggactcct acgatgtcac cgtggatgag

181 gagctgggcg agatctacct agtcaaaatt gagaagcgca aatactggct ccatgatgac

241 tggtacctga agtacatcac actgaagaca ccccacgggg actacatcga gttcccatgt

301 taccgctgga tcacaggcga gggcgagatt gtcctgaggg atggacgtgc aaaattggcc

361 cgagatgacc aaattcacat cctcaagcag cacagacgta aagaactgga ggcacggcaa

421 aaacagtatc gatggatgga gtggaacccc ggcttccctt tgagtattga tgccaaatgc

481 cacaaggatc tgccccgaga tatccagttt gatagtgaaa aaggagtgga ctttgttctg

541 aactactcaa aagcgatgga gaacctgttc atcaaccgct tcatgcacat gttccagtct

601 tcctggcacg actttgctga ctttgagaaa atcttcgtca aaatcagcaa cactatatct

661 ggatcgtggg atcctgccca gcggtcctat ctagaggtca ttctctccac agagcgagtc

721 aagaaccact ggcaggaaga cctcatgttt ggctaccagt tcctgaatgg ctgcaaccca

781 gtactcatca agcgctgcac agcgttgccc ccgaagctcc cagtgaccac agagatggtg

841 gagtgcagcc tagagcggca gctcagttta gaacaggaag tacaggaagg gaacattttc

901 atcgttgatt acgagctact ggatggcatc gatgctaaca aaactgaccc ctgtacacac

961 cagttcctgg ctgcccccat ctgcctgcta tataagaacc tagccaacaa gattgttccc

1021 attgccatcc agctcaacca aacccctgga gagagtaacc caatcttcct ccctacggat

1081 tcaaagtacg actggctttt ggccaaaatc tgggtgcgtt ccagtgactt ccacgtccat

1141 caaacgatca cccaccttct gcgcacgcat ctggtgtctg aggtgtttgg tatcgccatg

1201 taccgccagc tgcctgctgt gcatcccctt ttcaagctgc tggtagccca tgtgaggttc

1261 accattgcta tcaacactaa ggcccgggaa cagcttatct gcgagtatgg cctttttgac

1321 aaggccaatg ccaccggggg tggagggcac gtgcagatgg tgcagagggc tgtccaggat

1381 ctgacctatt cctccctgtg tttcccggag gccatcaagg cccggggcat ggacagcacg

1441 gaagacatcc ccttctactt ctatcgtgat gatggactgc tcgtgtggga ggctatccag

1501 tcgttcacaa tggaggtggt gagcatctac tatgagaacg accaggtggt ggaggaggac

1561 caggaactgc aggacttcgt gaaggatgtt tacgtgtacg gcatgcgggg caaaaaggcc

1621 tcaggtttcc ccaagtccat caagagcagg gagaagctgt ccgagtacct gacggtggtg

1681 atcttcacgg cctctgccca gcatgcagct gtaaacttcg gccagtatga ctggtgctcc

1741 tggatcccca acgctcctcc aactatgcgg gccccaccac ccacggccaa gggtgtggtc

1801 accatcgagc agatcgtgga tactctacca gaccgtggcc gatcatgttg gcatctaggt

1861 gcagtgtggg ccttgagcca gtttcaagaa aatgagctgt ttctaggcat gtacccagag

1921 gagcatttca ttgagaagcc agtgaaggaa gccatgatcc gattccgcaa gaacctggag

1981 gccatcgtca gcgtgatcgc cgagcgcaat aagaacaaaa agctccccta ctactacctg

2041 tcaccagaca ggattcccaa cagcgtagcc atctaa

SEQ ID NO: 10

Amino acid sequence of mouse ALOX5 encoded by the DNA sequence shown in SEQ ID NO: 9.

MPSYTVTVATGSQWFAGTDDYIYLSLIGSAGCSEKHLLDKAFYNDFERGAVDSYDVTVDE ELGEIYLVKIEKRKYWLHDDWYLKYITLKTPHGDYIEFPCYRWITGEGEIVLRDGRAKLA

RDDQIHILKQHRRKELEARQKQYRWMEWNPGFPLSIDAKCHKDLPRDIQFDSEKGVDFVL

NYSKAMENLFINRFMHMFQSSWHDFADFEKIFVKISNTISGSWDPAQRSYLEVILSTERV KNHWQEDLMFGYQFLNGCNPVLIKRCTALPPKLPVTTEMVECSLERQLSLEQEVQEGNIF IVDYELLDGIDANKTDPCTHQFLAAPICLLYKNLANKIVPIAIQLNQTPGESNPIFLPTD SKYDWLLAKIWVRSSDFHVHQTITHLLRTHLVSEVFGIAMYRQLPAVHPLFKLLVAHVRF TIAINTKAREQLICEYGLFDKANATGGGGHVQMVQRAVQDLTYSSLCFPEAIKARGMDST EDIPFYFYRDDGLLVWEAIQSFTMEVVSIYYENDQVVEEDQELQDFVKDVYVYGMRGKKA SGFPKSIKSREKLSEYLTWIFTASAQHAAVNFGQYDWCSWIPNAPPTMRAPPPTAKGW TIEQIVDTLPDRGRSCWHLGAVWALSQFQENELFLGMYPEEHFIEKPVKEAMIRFRKNLE AIVSVIAERNKNKKLPYYYLSPDRIPNSVAI

SEQ ED NO: 11 gi|6978492|ref|NM_012822.1| Rattus norvegicus arachidonate 5 -lipoxygenase (Alox5), mRNA i ctcttgagtg acagagtcaa gaatctggta aactgccacc tgaacttccc gggctcctgc

61 gcccacgcag cagcgctcac ttcccagagc catgccttcc tacactgtca ccgtagccac

121 cggtagccag tggttcgcgg gcaccgacga ctacatttac ctcagcctca ttggctctgc

181 aggctgcagt gagaagcatc ttcttgacaa agctttctac aatgacttcg agcgcggcgg

241 tcgcgactcc tatgacgtca ctgtggatga agaactgggt gagatctacc tagtcaaaat

301 cgagaagcgc aaatacaggc tccatgatga ctggtacttg aaatacatca cactgaagac

361 accccacgac tacatagagt tcccttgtta tcgttggatc acaggcgagg gcgagattgt

421 cctgagggat ggatgtgcaa aattggcccg agatgaccaa atccacatcc tcaagcagca

481 caggcggaaa gaactggaaa cacgtcagaa acagtatcga tggatggagt ggaaccccgg

541 cttccctttg agtattgatg ctaaatgcca caaggatctg ccccgagata tccagtttga

601 tagtgaaaag ggagtggact ttgttctgaa ctactcaaaa gcgatggaga acctgttcat

661 caatcgcttc atgcacatgt tccagtcttc ctggcatgac tttgctgact ttgagaaaat

721 cttcgtcaaa atcagcaaca ctatttctga gagagtcaag aaccactggc aagaggacct

781 catgtttggc taccagttcc tgaatggctg caacccagta ctcatcaagc gctgcacaga

841 gttgcctaag aagctcccag tgaccacaga aatggtggag tgcagcctag agcggcagct

901 cagtttagaa caggaagtac aggaagggaa cattttcatc gttgattacg aactactgga

961 tggcattgat gctaacaaaa ctgacccctg tacacaccag ttcctggccg cccccatctg

1021 cctgctgtat aagaacctag ccaacaagat tgttcccatc gccatccagc tcaaccaaac

1081 ccctggagag aagaacccaa ttttcctccc tacggactca aaatacgact ggcttttggc

1141 caaaatctgg gtgcgttcaa gtgacttcca tatccatcaa acaatcaccc atcttctccg

1201 cacacatctg gtgtctgagg tgttcggtat tgccatgtac cgccagctgc ctgctgtgca

1261 cccccttttc aagctgctgg tagcccatgt gaggttcacc attgccatca acactaaggc

1321 ccgggaacag cttaactgtg agtacggcct ttttgacaag gccaatgcca ccggaggtgg

1381 tgggcacgtg cagatggtgc agagagctgt ccaggacctg acctattcct ccctgtgctt

1441 cccggaggcc atcaaggccc ggggcatgga caacaccgag gacatcccct actacttcta

1501 tcgtgatgat ggactgctcg tgtgggaagc tatccagtcg ttcacaactg aggtggtaag

1561 catctactat gaggatgacc aggtggtgga ggaggaccag gaactgcagg acttcgtgaa

1621 ggatgtttac gtttatggca tgcggggcag aaaggcctca ggtttcccca agtccatcaa

1681 gagcagggag aaattgtctg agtacctgac ggtggtgatc ttcacagcct cggcccagca

1741 tgcagctgta aactttggcc agtatgactg gtgctcctgg atccccaacg ctcctccaac

1801 tatgcgggcc ccaccaccca cggccaaggg tgtggtcacc atcgagcaga ttgtggatac

1861 tctaccagac cgtggccgct catgttggca tctaggtgca gtgtgggcct tgagccagtt

1921 tcaagagaat gagctgtttc tgggcatgta cccagaggag catttcatcg agaagccagt

1981 gaaagaagcc atgattcgat tccgcaagaa cctggaggcc atcgtcagcg tgattgccga

2041 gcgcaataag aacaaaaagc tcccctacta ctacctgtca ccagacagat tccaaacagt

2101 gtagccatct aaggctttgc cgtccctgtc ccagcagctc tctgggcagg ccagtggctt

2161 gcctggcagg ctgtagatct tccagcagct ggtgcctctc ccaagctagc agtgccgctc

2221 ttgggcccag gtgtggttgt aaactaaagg ctgttctagg tgggaaattc acagagcttc

2281 agcacatgct acttcttcct gtcttcagtg acatagttca ggggcctccc atccagagca

2341 ggggtgtgcg gctgtgtccc ccagtccagc ttagtaacct cttcactcag tagcaacaga

2401 gtaagtgata atgttccact gggtcagggg tccatcattc tacttatgct tcctccaact

2461 gcctgcatac agtaggtgct tagagaaact tcttagatta agagtttgtt ataaaataaa

2521 gttcatttaa aacag SEQIDNO: 12 AminoacidsequenceofratALOX5encodedbytheDNAsequenceshowninSEQIDNO: 11.

MPSYTVTVATGSQWFAGTDDYIYLSLIGSAGCSEKHLLDKAFYNDFERGGRDSYDVTVDE ELGEIYLVKIEKRKYRLHDDWYLKYITLKTPHDYIEFPCYRWITGEGEIVLRDGCAKLAR DDQIHILKQHRRKELETRQKQYRWMEWNPGFPLSIDAKCHKDLPRDIQFDSEKGVDFVLN YSKAMENLFINRFMHMFQSSWHDFADFEKIFVKISNTISERVKNHWQEDLMFGYQFLNGC NPVLIKRCTELPKKLPVTTEMVECSLERQLSLEQEVQEGNIFIVDYELLDGIDANKTDPC THQFLAAPICLLYKNLANKIVPIAIQLNQTPGEKNPIFLPTDSKYDWLLAKIWVRSSDFH IHQTITHLLRTHLVSEVFGIAMYRQLPAVHPLFKLLVAHVRFTIAINTKΆREQLNCEYGL FDKANATGGGGHVQMVQRAVQDLTYSSLCFPEAIKARGMDNTEDIPYYFYRDDGLLVWEA IQSFTTEWSIYYEDDQWEEDQELQDFVKDVYVYGMRGRKASGFPKSIKSREKLSEYLT WIFTASAQHAAVNFGQYDWCSWIPNAPPTMRAPPPTAKGVVTIEQIVDTLPDRGRSCWH LGAVWALSQFQENELFLGMYPEEHFIEKPVKEAMIRFRKNLEAIVSVIAERNKNKKLPYY YLSPDRFQTV SEQIDNO: 13 gi|21735570|reflNM_001836.2|Homosapienschymase1,mastcell(CMAl),mRNA

1 agcatttgct caggcagcct ctctgggaag atgctgcttc ttcctctccc cctgctgctc

61 tttctcttgt gctccagagc tgaagctggg gagatcatcg ggggcacaga atgcaagcca

121 cattcccgcc cctacatggc ctacctggaa attgtaactt ccaacggtcc ctcaaaattt 181 tgtggtggtt tccttataag acggaacttt gtgctgacgg ctgctcattg tgcaggaagg 241 tctataacag tcacccttgg agcccataac ataacagagg aagaagacac atggcagaag 301 cttgaggtta taaagcaatt ccgtcatcca aaatataaca cttctactct tcaccacgat 361 atcatgttac taaagttgaa ggagaaagcc agcctgaccc tggctgtggg gacactcccc 421 ttcccatcac aattcaactt tgtcccacct gggagaatgt gccgggtggc tggctgggga 481 agaacaggtg tgttgaagcc gggctcagac actctgcaag aggtgaagct gagactcatg 541 gatccccagg cctgcagcca cttcagagac tttgaccaca atcttcagct gtgtgtgggc 601 aatcccagga agacaaaatc tgcatttaag ggagactctg ggggccctct tctgtgtgct 661 ggggtggccc agggcatcgt atcctatgga cggtcggatg caaagccccc tgctgtcttc 721 acccgaatct cccattaccg gccctggatc aaccagatcc tgcaggcaaa ttaatcctgg 781 atcc

SEQIDNO: 14

AminoacidsequenceofhumanCMAl encodedbytheDNAsequenceshowninSEQID NO: 13.

MLLLPLPLLLFLLCSRAEAGEIIGGTECKPHSRPYMAYLEIVTSNGPSKFCGGFLIRRNF VLTAAHCAGRSITVTLGAHNITEEEDTWQKLEVIKQFRHPKYNTSTLHHDIMLLKLKEKA SLTLAVGTLPFPSQFNFVPPGRMCRVAGWGRTGVLKPGSDTLQEVKLRLMDPQACSHFRD FDHNLQLCVGNPRKTKSAFKGDSGGPLLCAGVAQGIVSYGRSDAKPPAVFTRISHYRPWI NQILQAN

SEQ ID NO: 15 Amino acid sequence of human CMAl, a soluble active secreted form derived from SEQ ID NO: 14.

IIGGTECKPHSRPYMAYLEIVTSNGPSKFCGGFLIRRNFVLTAAHCAGRSITVTLGAHNI TEEEDTWQKLEVIKQFRHPKYNTSTLHHDIMLLKLKEKASLTLAVGTLPFPSQFNFVPPG RMCRVAGWGRTGVLKPGSDTLQEVKLRLMDPQACSHFRDFDHNLQLCVGNPRKTKSAFKG DSGGPLLCAGVAQGIVSYGRSDAKPPAVFTRISHYRPWINQILQAN SEQ ID NO: 16

gi|200956|gb|M73759.1 IMUSSEPRl Mouse serine proteinase, complete cds

1 agcagccctg aggaggccct ctgagaggat gcatcttctt gctcttcatc tgctgctcct

61 tctcctgggt tccagcacca aagctggaga gatcattgga ggcacggagt gcataccaca 121 ctcccgcccc tacatggcct atctggaaat tgtcacttct gagaactacc tgtcggcctg

181 cagtggcttc ctgataagaa gaaactttgt gctgactgca gctcactgtg cgggaaggtc

241 tataacagtc ctcctaggag cccataacaa aacatctaaa gaagacacgt ggcagaagct

301 tgaggtggaa aagcaattcc ttcatccaaa atatgatgag aatttggttg tccatgacat

361 catgctactg aagttgaagg agaaagccaa gctaacccta ggtgtgggaa ccctcccact 421 ctctgccaac ttcaacttta tcccacccgg gagaatgtgc agggcagttg gctggggcag

481 aacaaacgtg aatgagccag cctccgacac actgcaggaa gtaaagatga gactccagga

541 gccccaagcc tgcaaacact tcaccagttt tcgacacaat tcccagctgt gtgtgggcaa

601 ccccaagaag atgcaaaatg tatacaaggg agactctgga ggacctctgc tgtgtgctgg

661 gatagcccaa ggcattgcat cctatgtaca tcggaatgca aagccccctg ctgtctttac 721 cagaatctcc cattacaggc cctggatcaa taagatcttg agggagaatt aactctggag

781 cttttgccag cccgtgagga aatctggaac tggaatagtg caggttttgt gtgccatgtg

841 atctggcctg tctgtagttc ctgctgaagc cctgcctgat ccctgagctt ccagaaggtt

901 cttacaagtc acagaatgtt cctaaaagtc accatcttca ttaacctcaa taaagaccca

961 gattgtcgac tgaaaaaaaa SEQIDNO: 17

Amino acid sequence of mouse CMAl encoded by the DNA sequence shown in SEQ ID NO: 16.

MHLLTLHLLLLLLGSSTKAGEIIGGTECIPHSRPYMAYLEIVTSENYLSACSGFLIRRNF VLTAAHCAGRSITVLLGAHNKTSKEDTWQKLEVEKQFLHPKYDENLVVHDIMLLKLKEKA KLTLGVGTLPLSANFNFIPPGRMCRAVGWGRTNVNEPASDTLQEVKMRLQEPQACKHFTS FRHNSQLCVGNPKKMQNVYKGDSGGPLLCAGIAQGIASYVHRNRKPPAVFTRISHYRPWI NKILREN

SEQIDNO: 18 gi|6978666|ref]NM_013092.1|Rattusnorvegicuschymase1 (Cmal),mRNA 1 agcctgcaca gccctgagta gcccctcaga gaggatgaat ctccatgctc tgtgtctgct

61 gctccttctc ctgggttcca gcaccaaagc tggggagatc atcgggggca cggagtgcat

121 accacactcc cgcccctaca tggcctatct agaaattgtc acttctgaca attacctgtc

181 agcctgcagt ggcttcctga tcagacgaaa ctttgtgctg actgcagctc actgtgcagg

241 acggtctata accgtcctcc taggagctca taacaaaaca tataaagaag acacatggca 301 gaagctcgag gttgaaaagc aattcattca tccaaactat gataagcgtt tggttctcca 361 tgacatcatg ttactgaagt tgaaggagaa agccaagcta accctaggcg tgggaaccct 421 cccactctcg gccaacttca acttcattcc acccgggaga atgtgcaggg cagttggctg 481 gggcagaaca aacgtgaatg aaccagcctc tgacacactg caggaagtaa agatgagact 541 ccaggagccc caatcctgca aacacttcac cagttttcaa cacaagtccc agttgtgtgt 601 gggcaacccc aagaagatgc aaaatgtata caagggagac tctggaggac ctctcctgtg 661 tgctgggata gcccaaggca ttgcatccta cgtacatccg aatgcaaagc cccctgctgt 721 cttcaccaga atctcccatt acagaccctg gatcaataag atcttgaggg agaattaact 781 ctggatctcg ggccagtgtg tgaggaaatc tggagctgga atcgtgcagg ttttctgtga 841 catgggatct ggcctgtctg tagttcctgc tgaagccctt cctgatccct gagcttccag 901 aaggttctta caagtcacag aaagttccta aaagtcacca tcttcataaa cctcaataaa 961 gagccagatc ctagactgc

SEQIDNO: 19 AminoacidsequenceofratCMAl encodedbytheDNAsequenceshowninSEQIDNO: 18.

MNLHALCLLLLLLGSSTKAGEIIGGTECIPHSRPYMAYLEIVTSDNYLSACSGFLIRRNF VLTAAHCAGRSITVLLGAHNKTYKEDTWQKLEVEKQFIHPNYDKRLVLHDIMLLKLKEKA

KLTLGVGTLPLSANFNFIPPGRMCRAVGWGRTNVNEPASDTLQEVKMRLQEPQSCKHFTS FQHKSQLCVGNPKKMQNVYKGDSGGPLLCAGIAQGIASYVHPNAKPPAVFTRISHYRPWI NKILREN

SEQ ID NO: 20 gi|34328908|ref]NM_001394.4| Homo sapiens dual specificity phosphatase 4 (DUSP4), transcript variant 1, mRNA i gctgagcgcc ggaggagcgt aggcagggca gcgctggcgc cagcggcgac aggagccgcg

61 cgaccggcaa aaatacacgg gaggccgtcg ccgaaaagag tccgcggtcc tctctcgtaa

121 acacactctc ctccaccggc gcctccccct ccgctctgcg cgccgcccgg ctgggcgccc

181 gaggccgctc cgactgctat gtgaccgcga ggctgcggga ggaaggggac agggaagaag

241 aggctctccc gcgggagccc ttgaggacca agtttgcggc cacttctgca ggcgtccctt

301 cttagctctc gcctgcccct ttctgcagcc taggcggccc aggttctctt ctcttcctcg

361 cgcgcccagc cgcctcggtt cccggcgacc atggtgacga tggaggagct gcgggagatg

421 gactgcagtg tgctcaaaag gctgatgaac cgggacgaga atggcggcgg cgcgggcggc

481 agcggcagcc acggcaccct ggggctgccg agcggcggca agtgcctgct gctggactgc

541 agaccgttcc tggcgcacag cgcgggctac atcctaggtt cggtcaacgt gcgctgtaac

601 accatcgtgc ggcggcgggc taagggctcc gtgagcctgg agcagatcct gcccgccgag

661 gaggaggtac gcgcccgctt gcgctccggc ctctactcgg cggtcatcgt ctacgacgag

721 cgcagcccgc gcgccgagag cctccgcgag gacagcaccg tgtcgctggt ggtgcaggcg

781 ctgcgccgca acgccgagcg caccgacatc tgcctgctca aaggcggcta tgagaggttt

841 tcctccgagt acccagaatt ctgttctaaa accaaggccc tggcagccat cccacccccg

901 gttcccccca gcgccacaga gcccttggac ctgggctgca gctcctgtgg gaccccacta

961 cacgaccagg ggggtcctgt ggagatcctt cccttcctct acctcggcag tgcctaccat

1021 gctgcccgga gagacatgct ggacgccctg ggcatcacgg ctctgttgaa tgtctcctcg

1081 gactgcccaa accactttga aggacactat cagtacaagt gcatcccagt ggaagataac

1141 cacaaggccg acatcagctc ctggttcatg gaagccatag agtacatcga tgccgtgaag

1201 gactgccgtg ggcgcgtgct ggtgcactgc caggcgggca tctcgcggtc ggccaccatc

1261 tgcctggcct acctgatgat gaagaaacgg gtgaggctgg aggaggcctt cgagttcgtt

1321 aagcagcgcc gcagcatcat ctcgcccaac ttcagcttca tggggcagct gctgcagttc

1381 gagtcccagg tgctggccac gtcctgtgct gcggaggctg ctagcccctc gggacccctg

1441 cgggagcggg gcaagacccc cgccaccccc acctcgcagt tcgtcttcag ctttccggtc

1501 tccgtgggcg tgcactcggc ccccagcagc ctgccctacc tgcacagccc catcaccacc

1561 tctcccagct gttagagccg ccctgggggc cccagaacca gagctggctc ccagcaaggg

1621 taggacgggc cgcatgcggc agaaagttgg gactgagcag ctgggagcag gcgaccgagc

1681 tccttcccca tcatttctcc ttggccaacg acgaggccag ccagaatggc aataaggact

1741 ccgaatacat aataaaagca aacagaacac tccaacttag agcaataacc ggtgccgcag

1801 cagccaggga agaccttggt ttggtttatg tgtcagtttc acttttccga tagaaatttc

1861 ttacctcatt tttttaagca gtaaggcttg aagtgatgaa acccacagat cctagcaaat

1921 gtgcccaacc agctttacta aagggggagg aagggagggc aaagggatga gaagacaagt

1981 ttcccagaag tgcctggttc tgggtacttg tccctttgtt gtcgttgttg tagttaaagg

2041 aatttcattt ttaaaagaaa tcttcgaagg tgtggttttc atttctcagt caccaacaga

2101 tgaataatta tgcttaataa taaagtattt attaagactt tcttcagagt atgaaagtac

2161 aaaaagtcta gttacagtgg atttagaata tatttatgtt gatgtcaaac agctgagcac

2221 cgtagcatgc agatgtcaag gcagttagga agtaaatggt gtcttgtaga tatgtgcaag

2281 gtagcatgat gagcaacttg agtttgttgc cactgagaag caggcgggtt gggtgggagg

2341 aggaagaaag ggaagaatta ggtttgaatt gctttttaaa aaaaaaagaa aagaaaaaga

2401 cagcatctca ctatgttgcc aaggctcatc ttgagaagca ggcgggttgg gtgggaggag

2461 gaagaaaggg aagaattagg tttgaattgc ttttttaaaa aaaaa

SEQIDNO:21 Amino acid sequence of human DUSP4 encoded by the DNA sequence shown in SEQ ID NO: 20.

MVTMEELREMDCSVLKRLMNRDENGGGAGGSGSHGTLGLPSGGKCLLLDCRPFLAHSAGY ILGSVNVRCNTIVRRRAKGSVSLEQILPAEEEVRARLRSGLYSAVIVYDERSPRAESLRE DSTVSLWQALRRNAERTDICLLKGGYERFSSEYPEFCSKTKALAAIPPPVPPSATEPLD LGCSSCGTPLHDQGGPVEILPFLYLGSAYHAARRDMLDALGITALLNVSSDCPNHFEGHY QYKCIPVEDNHKADISSWFMEAIEYIDAVKDCRGRVLVHCQAGISRSATICLAYLMMKKR VRLEEAFEFVKQRRSIISPNFSFMGQLLQFESQVLATSCAAEAASPSGPLRERGKTPATP TSQFVFSFPVSVGVHSAPSSLPYLHSPITTSPSC SEQ ID NO: 22 gi|21536335|reflNM_057158.2| Homo sapiens dual specificity phosphatase 4 (DUSP4), transcript variant 2, rnRNA i gcagttcaga cccccccaca cccatcaaag agccgctcct cccccccgca ggcgccttcg

61 ccgcctccct cccttccttt cctttccgct cctcttccga cctgtccacc cgggaggaag

121 ggagctggaa agggggcgga aacctctccc ctccaaaaag cacaacaaaa ctgttcagtg

181 cggaggagcc gggttcgccc ctgccggaca gcggggggct ttgttccccg cagttgtttc

241 ctgcccattt gacctgtcag ctgctgggga aacgctgctg ttgacctttg gttgaactgc

301 taaggcgatt ttgctgattt ttctttcttt ttccgcgagg gctgtctttt gctcctccaa

361 atgagcccag tccccctccc ttctccccaa agcgctccaa gagaaagtgc caggaagggg

421 cttgtcccgg aaggcctggc ggctgagcgg ggccaggtcc tggttaggcc accagggtgg

481 gcgtccgcgc cattgtttga gcttgtcggc gctggtggga gagatgaggg caattcctct

541 gggacgcaag tcccctcgaa tggccggggc tggccgggat gttccccgca cggcgctgcc

601 ctcgagtccc cccgatggag agcgcgggcg cgccttcctt cgctggcgtc caaacccggg

661 accagctaga acacagcagg gctgggactg ggttccagcc ccacgtggag tctggatttg

721 ttttgttgtg ttttgctttc cttcctggaa gaaatcccga ggggaccgcc ctagagcggc

781 agctccagga cctcggccct tgggcttccg ggggtgcagc cacttaggcc ccgctcccgg

841 ggagagaggg attatttttt aagatttatc cccagggcgc gcggcatttc cctgtccctc

901 gtgaatcccg ttgagagtcc tccctcccca acctcctcca tttccccagc cagaccgatt

961 cgagagccct ggagattctg ggcgaggcta gtgactgggt agtacaggcc tctagcccca

1021 ccattgctct ctctgtcttc agttccccag gagggcaatg gcatcaaaca gcacagctct

1081 gggggatgtc aatattgcat accttttcta cctaaaggga aaatgactcg cttttctgct

1141 tgcaaatatg gtagtttctg cttacaaatg taatacaatg cccatgacag ccaaggactg

1201 gaagcataag ttgctaggtc ttacaggtga ttttttacaa tgaagcaaac tcactatgtt

1261 agacaccatt tacattggat gtctccaact aacaaaagta actaaagaca gatgtaggtg

1321 taaattgaga gtgaaatttg accctttaga ccgtcacaac ttccttgggc ttatcctggg

1381 tgcttatagg agaggtgggc tccacccaca aaaatggact gctcagaaaa atgagggaga

1441 gagaaagggt ggccactttc ccgagccaag aaattccttg aaaaaaaatc agaacatctg

1501 aaaccagaga gccgatttcc ttaccgggag gcagttcctg gctaacgaag aggaagcacg

1561 atgggaagaa aagttcactc caacggaagc cagtttgctg aacatagcag atcgcccagg

1621 aggactggga gagactgcaa accagttcga gcccccagca tggcgttagg tgtcagccag

1681 ctggcaggaa ggtccaggtg tctgtgttca gagtctcaag gcggctatga gaggttttcc

1741 tccgagtacc cagaattctg ttctaaaacc aaggccctgg cagccatccc acccccggtt

1801 ccccccagtg ccacagagcc cttggacctg ggctgcagct cctgtgggac cccactacac

1861 gaccaggggg gtcctgtgga gatccttccc ttcctctacc tcggcagtgc ctaccatgct

1921 gcccggagag acatgctgga cgccctgggc atcacggctc tgttgaatgt ctcctcggac

1981 tgcccaaacc actttgaagg acactatcag tacaagtgca tcccagtgga agataaccac

2041 aaggccgaca tcagctcctg gttcatggaa gccatagagt acatcgatgc cgtgaaggac

2101 tgccgtgggc gcgtgctggt gcactgccag gcgggcatct cgcggtcggc caccatctgc

2161 ctggcctacc tgatgatgaa gaaacgggtg aggctggagg aggccttcga gttcgttaag

2221 cagcgccgca gcatcatctc gcccaacttc agcttcatgg ggcagctgct gcagttcgag

2281 tcccaggtgc tggccacgtc ctgtgctgcg gaggctgcta gcccctcggg acccctgcgg

2341 gagcggggca agacccccgc cacccccacc tcgcagttcg tcttcagctt tccggtctcc

2401 gtgggcgtgc actcggcccc cagcagcctg ccctacctgc acagccccat caccacctct

2461 cccagctgtt agagccgccc tgggggcccc agaaccagag ctggctccca gcaagggtag

2521 gacgggccgc atgcgggcag aaagttggga ctgagcagct gggagcaggc gaccgagctc 2581 cttccccatc atttctcctt ggccaacgac gaggccagcc agaatggcaa taaggactcc 2641 gaatacataa taaaagcaaa cagaacactc caacttagag caataacggc tgccgcagca 2701 gccagggaag accttggttt ggtttatgtg tcagtttcac ttttccgata gaaatttctt 2761 acctcatttt tttaagcagt aaggcttgaa gtgatgaaac ccacagatcc tagcaaatgt 2821 gcccaaccag ctttactaaa gggggaggaa gggagggcaa agggatgaga agacaagttt 2881 cccagaagtg cctggttctg tgtacttgtc cctttgttgt cgttgttgta gttaaaggaa 2941 tttcattttt taaaagaaat cttcgaaggt gtggttttca tttctcagtc accaacagat 3001 gaataattat gcttaataat aaagtattta ttaagacttt cttcagagta tgaaagtaca 3061 aaaagtctag ttacagtgga tttagaatat atttatgttg atgtcaaaca gctgagcacc 3121 gtagcatgca gatgtcaagg cagttaggaa gtaaatggtg tcttgtagat atgtgcaagg 3181 tagcatgatg agcaacttga gtttgttgcc actgagaagc aggcgggttg ggtgggagga 3241 ggaagaaagg gaagaattag gtttgaattg ctttttaaaa aaaaaagaaa agaaaaagac 3301 agcatctcac tatgttgcca aggctcatct tgagaagcag gcgggttggg tgggaggagg 3361 aagaaaggga agaattaggt ttgaattgct tttttaaaaa aaaa SEQIDNO:23

Amino acid sequence of human DUSP4 variant ORF number 1 encoded by the DNA sequence shown in SEQ ID NO: 22.

MGRKVHSNGSQFAEHSRSPRRTGRDCKPVRAPSMALGVSQLAGRSRCLCSESQGGYERFS SEYPEFCSKTKALAAIPPPVPPSATEPLDLGCSSCGTPLHDQGGPVEILPFLYLGSAYHA ARRDMLDALGITALLNVSSDCPNHFEGHYQYKCIPVEDNHKADISSWFMEAIEYIDAVKD CRGRVLVHCQAGISRSATICLAYLMMKKRVRLEEAFEFVKQRRS11SPNFSFMGQLLQFE SQVLATSCAAEAASPSGPLRERGKTPATPTSQFVFSFPVSVGVHSAPSSLPYLHSPITTS PSC

SEQ ID NO: 24 gi|31581570|ref]NM_l 76933.31 Mus musculus dual specificity phosphatase 4 (Dusp4), mRNA i ggtcacttct gcaggcgccc tcttagccct cgcctggttc cttcttgtta gcctagctgg

61 ctccggtgcc cttggccttc tccagctagc tccccagctt actgcgtttt gccggcgaca

121 tggtgacgat ggaggaactg cgggagatgg actgcagcgt gctcaaaagg ctgatgaacc

181 gggatgagaa cggcggcggc ggcagcgcgg gcggcaacgg cagcggcagc cacggcgcct

241 tggggctgct gagcggcggc aagtgcctgc tgctggactg caggccgttt ctggctcaca

301 gcgcgggcta catccgaggc tcggtgaacg tgcgctgcaa taccatcgtg cggcggaggg

361 ccaagggctc cgtgagcctg gagcagatcc tgcccgccga ggaagaggtg cgtgcccgcc

421 tgcgctctgg cctctactcg gctgtcatcg tctacgacga gcgcagcccg cgcgccgaga

481 gtctccggga ggacagcacg gtgtcgctgg tcgtgcaggc gttgcgccgg aacgcggagc

541 gcacggacat ctgcctgctt aaaggtggct atgagaggtt ttcttctgaa tacccagaat

601 tctgctctaa aaccaaggcc ctggccgcca tcccaccccc tgtacctccc agcaccaatg

661 agtccttgga cctgggctgc agctcctgtg gaaccccgct gcacgaccag gggggccccg

721 tggaaatcct ccctttcctc tacctcggca gtgcctacca tgctgcccgc agggacatgt

781 tggatgccct ggggatcacg gccctcctga atgtctcttc agactgtccc aatcactttg

841 agggtcatta ccagtacaag tgcatccccg tcgaagacaa ccacaaggcc gacatcagct

901 cctggttcat ggaagccatc gagtacatcg acgcagtaaa ggactgtcga gggcgagtgc

961 tggttcactg ccaggccggc atctcccgat cagccaccat ctgcctggcc tacctgatga

1021 tgaagaagcg ggtgaggctg gaggaggctt ttgagttcgt caagcagcgc cgaagcatca

1081 tctcgcccaa cttcagcttc atgggccagt tgctgcagtt tgagtctcag gtgctcacca

1141 cgtcctgcgc cgccgaggct gccagccctt ctgggcccct tcgggagagg ggaaaggcca

1201 ccccgacccc cacctcgcag ttcgtcttca gcttccctgt gtctgtgggc gtgcacgcgg

1261 cccccagtaa cctgccgtac ctgcacagcc ccatcaccac ctcccccagc tgttaggact

1321 cgtctctgga ccccaaatcc agagtcggcc cccagccagt tgccagccac ctgtgaacag

1381 caaataggga ctgaccagtg ggggatcagg tgaccaggct ccgtctccat ttctccttgg

1441 ccaaccacag ggccagctag gatggcaata acgactttga atacacatta aaaacaaaca

1501 caactaaaca ctctaacata agcaataacg gcggtttccg ctgccagaga agacttggtt 1561 tctgtgtcag tttttacttt gcaggtagaa atttacctca ttattattat tattaaaaaa 1621 gcaatcaagc ttgaaagtta tgaaacccca cagatcctgg caaatgtgcg caaccaattt 1681 ttattgagtg gagagggaaa ggaaagagga gaaaaaatga gtttgccagg aaagtgcctg 1741 gttctgtgtg tgtctgttct cctgttgttg aactcacagg aattttgttc tagatccttc 1801 taggccacag tattatactt agtcgtcaac tggataatca cttactgttt aatgcatatt 1861 gagaacctca gcatgtgtgt gcaggagtct agtgactctg ggagatattt ctgttgaggt 1921 cacacagtcg agcagagaaa cacacaggtg tgtgagcagt gagaggagcg tcgggtaggt 1981 ggtcaccatg gttaccatca gacgcagggt gacatgcaag gaaaaaggtt tatggttggt 2041 cacttttgca gctggcccct gggcccactg acccagccac gtgagatttt tctctccagc 2101 ggtctgtttg gctggggata gagtggtttc ttcccacttg gcctaggatc tggctattgg 2161 tctgtggtaa acgccatctt taccaaggtg ctcctggaaa actgggtgcc gttcagattt 2221 tcctgccgtg aatcatttgg taaggccaga tcagaaccag atcactgaag atgaactaaa 2281 aatgaatctc cctctcgcgg atacattggg tgtttcagat ttagcagttt acttgaagta 2341 tacataccaa gaaattcttg ttacaaaatc tggtgaatac tctgaaacgc cctccctctt 2401 ttgaataaaa agatacgcat atgcctgt

SEQIDNO:25

Amino acid sequence of mouse DUSP4 encoded by the DNA sequence shown in SEQ ID NO: 24.

MVTMEELREMDCSVLKRLMNRDENGGGGSAGGNGSGSHGALGLLSGGKCLLLDCRPFLAH SAGYIRGSVNVRCNTIVRRRAKGSVSLEQILPAEEEVRARLRSGLYSAVIVYDERSPRAE

SLREDSTVSLVVQALRRNAERTDICLLKGGYERFSSEYPEFCSKTKALAAIPPPVPPSTN

ESLDLGCSSCGTPLHDQGGPVEILPFLYLGSAYHAARRDMLDALGITALLNVSSDCPNHF

EGHYQYKCIPVEDNHKADISSWFMEAIEYIDAVKDCRGRVLVHCQAGISRSATICLAYLM

MKKRVRLEEAFEFVKQRRSIISPNFSFMGQLLQFESQVLTTSCAAEAASPSGPLRERGKA TPTPTSQFVFSFPVSVGVHAAPSNLPYLHSPITTSPSC

SEQ ID NO: 26 gi|25742821|ref|NM_022199.1| Rattus norvegicus dual specificity phosphatase 4 (Dusp4), mRNA i atggtgacga tggaggaact gcgggagatg gactgcagcg tgctcaaaag gctgatgaac

61 cgagatgaga acggcggcac ggcgggcagc agcggcggca gccacggcgc cctggggctg 121 ctgagcggcg gcaagtgctt gctgctggac tgcaggccgt ttctggctca cagcgcgggc 181 tacatccgag gctcggtgaa cgtgcgctgc aataccatcg tgcggcggag ggccaagggc 241 tccgtgagcc tggagcagat tctgcccgcc gaggaagagg tgcgcgcccg cctgcgctct 301 ggcctctact cggctgtcat cgtctacgat gagcgcagcc cgcgcgccga gagtctccgg 361 gaggacagca cagtgtcgct ggtcgtgcag gcgttgcgcc ggaacgcgga gcgcacagac 421 atctgcctgc ttaaaggtgg ctatgagagg ttttcttctg agtacccaga attctgctct 481 aaaactaagg ccctggccgc catcccaccc cccgtacctc ccagcacaaa tgagtccttg 541 gatctgggct gcagctcctg tgggacccca ctgcacgacc aggggggtcc tgtggagatc 601 cttcctttcc tctacctcgg cagtgcctac cacgctgccc gcagggacat gcttgatgcc 661 ctggggatca cggctctact gaatgtctcc tcagactgcc ccaatcactt tgagggacat 721 taccagtaca agtgcatccc ggtagaagat aaccacaagg ctgacatcag ctcctggttc 781 atggaagcca tcgaatacat agacgcagtg aaggactgcc gagggcgagt gctggttcac 841 tgccaggccg gcatctctag atcagccacc atctgcctgg cctacctgat gatgaagaaa 901 cgggtgaggc tggaggaggc tttcgagttc gtcaagcagc gccgtagcat catctcgccc 961 aacttcagct tcatgggcca gttgctgcag ttcgagtctc aggtgctcac cacgtcctgc 1021 gcagcggagg ccgccagccc ttccgggccc ctgcgggaga gggggaaggc cactcccacc 1081 cccacctcgc agttcgtctt cagcttcccc gtgtccgtgg gtgtgcacgc ggctcccagt 1141 aacctgccgt acctgcacag ccccatcacc acctccccca gctgttag

SEQIDNO:27 Amino acid sequence of rat DUSP4 encoded by the DNA sequence shown in SEQ ID NO: 26.

MVTMEELREMDCSVLKRLMNRDENGGTAGSSGGSHGALGLLSGGKCLLLDCRPFLAHSAG YIRGSVNVRCNTIVRRRAKGSVSLEQILPAEEEVRARLRSGLYSAVIVYDERSPRAESLR EDSTVSLVVQALRRNAERTDICLLKGGYERFSSEYPEFCSKTKALAAIPPPVPPSTNESL DLGCSSCGTPLHDQGGPVEILPFLYLGSAYHAARRDMLDALGITALLNVSSDCPNHFEGH YQYKCIPVEDNHKADISSWFMEAIEYIDAVKDCRGRVLVHCQAGISRSATICLAYLMMKK RVRLEEAFEFVKQRRSIISPNFSFMGQLLQFESQVLTTSCAAEAASPSGPLRERGKATPT PTSQFVFSFPVSVGVHAAPSNLPYLHSPITTSPSC

SEQ ID NO: 28 gi|8923863|ref]NM_018479.1| Homo sapiens enoyl Coenzyme A hydratase domain containing 1 (ECHDCl), mRNA i ggcacgagcg gcacgagcgg agggcgcctc gcggcaggag cgggatttcc ggggtcacgg

61 gaaccggcag gggaacggga taaagttccc ggagaaagga aaggagagcg tgggatagta

121 aaagagaaga cgcggagaag aggagaggac ctacaagaac ggaggacagg ggcgcacgat

181 ggtcccgggg ggagcggaaa caaaggcacg caaaacggaa aagcgtgtgt aggggagcgg

241 aaaaggaagt caccaccgtg gcctgcgacg aaatggcgaa aagtcttttg aagacagcct

301 ctctgtctgg aaggacaaaa ttgctacatc aaacaggatt gtcactttat agtacatccc

361 atggatttta tgaggaagaa gtgaaaaaaa cacttcagca gtttcctggt ggatccattg

421 accttcagaa ggaagacaat ggcattggca ttcttactct gaacaatcca agtagaatga

481 atgccttttc aggtgttatg atgctacaac ttctggaaaa agtaattgaa ttggaaaatt

541 ggacagaggg gaaaggcctc attgtccgtg gggcaaaaaa tactttctct tcaggatctg

601 atctgaatgc tgtgaaaatc accataggaa tctcccagag gagacttcct ttaataagtg

661 ttgcgctggt tcaaggttgg gcattgggtg gaggagcaga atttactaca gcatgtgatt

721 tcaggttaat gactccagag agtaagatca gattcgtcca caaagagatg ggcataatac

781 caagctgggg tggcaccacc cggctagttg aaataatcgg aagtagacaa gctctcaaag

841 tgttgagtgg ggcccttaaa ctggattcaa aaaatgctct aaacatagga atggttgaag

901 aggtcttgca gtcttcagat gaaactaaat ctctagaaga ggcacaagaa tggctaaagc

961 aattcatcca agggccaccg gaagtaatta gagctttgaa aaaatctgtt tgttcaggca

1021 gagagctata tttggaggaa gcattacaga acgaaagaga tcttttagga acagtttggg

1081 gtgggcctgc aaatttagag gctattgcta agaaaggaaa atttaataaa taattggttt

1141 ttcgtgtgga tgtactccaa gtaaagctcc agtgactaat atgtataaat gttaaatgat

1201 attaaatatg aacatcagtt aaaaaaaaaa ttctttaagg ctactattaa tatgcagact

1261 tacttttaat catttgaaat ctgaactcat ttacctcatt tcttgccaat tactcccttg

1321 ggtatttact gcgtaattgg aacatttact aaaataacac ttttggctta aaaaaaaaaa

1381 aaaaaaaaaa aaaaaaaaaa aa

SEQIDNO:29

Amino acid sequence of human ECHDCl encoded by the DNA sequence shown in SEQ ID NO: 28.

MAKSLLKTASLSGRTKLLHQTGLSLYSTSHGFYEEEVKKTLQQFPGGSIDLQKEDNGIGI LTLNNPSRMNAFSGVMMLQLLEKVIELENWTEGKGLIVRGAKNTFSSGSDLNAVKITIGI SQRRLPLISVALVQGWALGGGAEFTTACDFRLMTPESKIRFVHKEMGIIPSWGGTTRLVE IIGSRQALKVLSGALKLDSKNALNIGMVEEVLQSSDETKSLEEAQEWLKQFIQGPPEVIR ALKKSVCSGRELYLEEALQNERDLLGTVWGGPANLEAIAKKGKFNK

SEQ ID NO: 30 gi|21740233|emb|AL834469.1|HSM805572 Homo sapiens mRNA; cDNA DKFZp762M1110 (from clone DKFZp762Ml 110)

1 cgggaaccgg caggggaacg ggataaagtt cccggagaaa ggaaaggaga gcgtgggata 61 gtaaaagaga agacgcggag aagaggagag gacctacaag aacggaggac aggggcgcac

121 gatggtcccg gggggagcgg aaacaaaggc acgcaaaacg gaaaagcgtg tgtaggggag

181 cggaaaagaa agtcaccacc gtggcctgcg acgaaatggc gaaaagtctt ttgaagacag

241 cctctctgtc tggaaggaca aaattgctac atcaaacagg attgtcactt tatagtacat

301 cccatggatt ttatgaggaa gaagtgaaaa aaacacttca gcagtttcct ggtggatcca

361 ttgaccttca gaaggaagac aatggcattg gcattcttac tctgaacaat ccaagtagaa

421 tgaatgcctt ttcaggtgtt atgatgctac aacttctgga aaaagtaatt gaattggaaa

481 attggacaga ggggaaaggc ctcattgtcc gtggggcaaa aaatactttc tcttcaggat

541 ctgatctgaa tgctgtgaaa tcactaggaa ctccagagga tggaatggcc gtatgcatgt

601 tcatgcaaaa caccttaaca agatttatga gacttccttt aataagtgtt gcgctggttc

661 aaggttgggc attgggtgga ggagcagaat ttactacagc atgtgatttc aggttaatga

721 ctccagagag taagatcaga ttcgtccaca aagagatggg cataatacca agctggggtg

781 gcaccacccg gctagttgaa ataatcggaa gtagacaagc tctcaaagtg ttgagtgggg

841 cccttaaact ggattcaaaa aatgctctaa acataggaat ggttgaagag gtcttgcagt

901 cttcagatga aactaaatct ctagaagagg cacaagaatg gctaaagcaa ttcatccaag

961 ggccaccgga agtaattaga gctttgaaaa aatctgtttg ttcaggcaga gagctatatt

1021 tggaggaagc attacagaac gaaagagatc ttttaggaac agtttggggt gggcctgcaa

1081 atttagaggc tattgctaag aaaggaaaat ttaataaata attggttttt cgtgtggatg

1141 tactccaagt aaagctccag tgactaatat gtataaatgt taaatgatat taaatatgaa

1201 catcagaatt actttgaagg ctactattaa tatgcagact tacttttaat catttgaata

1261 tctgaactca tttacctcat ttcttgccaa ttactcactt gggtatttac tgcgtaatct

1321 ggaacattta gctaaaatat acacttttgg cttaaaaatt attgctgtca attccaataa

1381 taattcttag cttataacca aagagcagtg tttaaaagga gagcttctat acaaaaccta

1441 ttcctggcgt tacttttcat acaatttttg ttctgtttta cctggaaata atttaccaaa

1501 ataactgagt gttgctgcta aagaacaaaa gtggggaggt atcagggaac aagaaaacaa

1561 gaaagggtat gatcaatcat tttcttctgc tccaaacagc tggagtaaaa ttcatgggaa

1621 atggcccttc atttaaaaaa agatgtacct cactacccac tacaaatttg gaactttgtt

1681 cttttcaata attagttttc tattgtaaat tacctactaa acagtggtag ccatgacatg

1741 gaaagtcaac tgattctaca attggacatt catttgtgtg ccctggaatt tccaactagt

1801 aataaacaac tactgttgat gtagttttaa accacttgaa gggactcatg aagcatcctg

1861 caacataaat ttgcattttt acatcagatt tctttttttt cctgaaaaac aactaacctt

1921 ctaacaacta tctttcaaaa gtaaatgtaa taaaaatgca caacataaaa tgtttatgat

1981 cccagcaata cactttttaa aaaatgtgaa agtcaaagaa ttaagttcta gttctgactc

2041 atcacaagag gtcaaaagta tttgctactg taacattcaa ttcacatttg agaatcatgg

2101 taaaaataac ttgcatttgc cttaccatca tgatcctact gttgagttag gaaaatatgg

2161 ttagacagac tcacattact ttttttcaga ggtaaactct agattactgt gtcaacccaa

2221 tactatttgg ccatagatgt aaaaactacc aaataaaagt ggattttgtg gtctacaaaa

2281 aaaaaaaaaa aaag

SEQIDNO: 31 Amino acid sequence of human ECHDCl variant ORF number 1 encoded by the DNA sequence shown in SEQ ID NO: 30.

MAKSLLKTASLSGRTKLLHQTGLSLYSTSHGFYEEEVKKTLQQFPGGSIDLQKEDNGIGI LTLNNPSRMNAFSGVMMLQLLEKVIELENWTEGKGLIVRGAKNTFSSGSDLNAVKSLGTP EDGMAVCMFMQNTLTRFMRLPLISVALVQGWALGGGAEFTTACDFRLMTPESKIRFVHKE MGIIPSWGGTTRLVEIIGSRQALKVLSGALKLDSKNALNIGMVEEVLQSSDETKSLEEAQ EWLKQFIQGPPEVIRALKKSVCSGRELYLEEALQNERDLLGTVWGGPANLEAIAKKGKFN K

SEQ ID NO: 32 gi|7689034|gb|AF220192.1|AF220192 Homo sapiens uncharacterized hypothalamus protein HCDASE mRNA, complete cds

1 ggcacgagcg gcacgagcgg agggcgcctc gcggcaggag cgggatttcc ggggtcacgg 61 gaaccggcag gggaacggga taaagttccc ggagaaagga aaggagagcg tgggatagta 121 aaagagaaga cgcggagaag aggagaggac ctacaagaac ggaggacagg ggcgcacgat

181 ggtcccgggg ggagcggaaa caaaggcacg caaaacggaa aagcgtgtgt aggggagcgg

241 aaaaggaagt caccaccgtg gcctgcgacg aaatggcgaa aagtcttttg aagacagcct

301 ctctgtctgg aaggacaaaa ttgctacatc aaacaggatt gtcactttat agtacatccc 361 atggatttta tgaggaagaa gtgaaaaaaa cacttcagca gtttcctggt ggatccattg

421 accttcagaa ggaagacaat ggcattggca ttcttactct gaacaatcca agtagaatga

481 atgccttttc aggtgttatg atgctacaac ttctggaaaa agtaattgaa ttggaaaatt

541 ggacagaggg gaaaggcctc attgtccgtg gggcaaaaaa taGtttctct tcaggatctg

601 atctgaatgc tgtgaaaatc accataggaa tctcccagag gagacttcct ttaataagtg 661 ttgcgctggt tcaaggttgg gcattgggtg gaggagcaga atttactaca gcatgtgatt

721 tcaggttaat gactccagag agtaagatca gattcgtcca caaagagatg ggcataatac

781 caagctgggg tggcaccacc cggctagttg aaataatcgg aagtagacaa gctctcaaag

841 tgttgagtgg ggcccttaaa ctggattcaa aaaatgctct aaacatagga atggttgaag

901 aggtcttgca gtcttcagat gaaactaaat ctctagaaga ggcacaagaa tggctaaagc 961 aattcatcca agggccaccg gaagtaatta gagctttgaa aaaatctgtt tgttcaggca

1021 gagagctata tttggaggaa gcattacaga acgaaagaga tcttttagga acagtttggg

1081 gtgggcctgc aaatttagag gctattgcta agaaaggaaa atttaataaa taattggttt

1141 ttcgtgtgga tgtactccaa gtaaagctcc agtgactaat atgtataaat gttaaatgat

1201 attaaatatg aacatcagtt aaaaaaaaaa ttctttaagg ctactattaa tatgcagact 1261 tacttttaat catttgaaat ctgaactcat ttacctcatt tcttgccaat tactcccttg

1321 ggtatttact gcgtaattgg aacatttact aaaataacac ttttggctta aaaaaaaaaa

1381 aaaaaaaaaa aaaaaaaaaa aa

SEQ ID NO: 33

Amino acid sequence of human ECHDCl variant ORF number 2 encoded by the DNA sequence shown in SEQ ID NO: 32.

MAKSLLKTASLSGRTKLLHQTGLSLYSTSHGFYEEEVKKTLQQFPGGSIDLQKEDNGIGI LTLNNPSRMNAFSGVMMLQLLEKVIELENWTEGKGLIVRGAKNTFSSGSDLNAVKITIGI SQRRLPLISVALVQGWALGGGAEFTTACDFRLMTPESKIRFVHKEMGIIPSWGGTTRLVE IIGSRQALKVLSGALKLDSKNALNIGMVEEVLQSSDETKSLEEAQEWLKQFIQGPPEVIR ALKKSVCSGRELYLEEALQNERDLLGTVWGGPANLEAIAKKGKFNK

SEQIDNO:34 gi|31542450|ref|NM_025855.2|MusmusculusenoylCoenzymeAhydratasedomain containing1 (Echdcl),mRNA

1 ttggggaaat cctgaggcgt tgcanagaac gtgggaaaat ccgctaaatt ggcaatttca 61 aaggatgaaa aggtgtgagg tcaattctaa gccgatttct gaatattttg gaatcccttg 121 tgagaaccaa gaaatggcaa aatgtctttt gacttcatct ctgtctgtaa gaacaaaact 181 cttacaaaca ggagtgtcgc tttataatac gagtcatggc ttccacgagg aggaagtgaa 241 gaagatactg gagcagtttc ctggtggatc cattgacctc ctaaagaagc agaacggcat 301 tggcattctg acgctaaaca accccaataa aatgaatgcc ttctcaggtg tcatgatgct 361 acaacttttg gaaagggtaa ttgaattaga aaattggaca gaagggaaag gcctcattat 421 ccatggagca aaaaatactt tctgctcagg atctgatctg aatgctgtga aggcactctc 481 cactccagaa agtggagtgg ccttatctat gttcatgcaa aacacgttaa caagatttat 541 gagactaccg ttaataagtg ttgctctggt tcaaggctgg gcaatgggtg gaggagcaga 601 acttactaca gcatgtgatt tcaggttgat gactgaggaa agtgtgatca gatttgtcca 661 caaggagatg ggtatagttc caagctgggg tggtaccagc cgtctggttg aaatcattgg 721 cagcagacaa gctctcaaag tgttaagtgg gactctcaaa ctggattcca aggaagcttt 781 aaatataggc ttgactgatg aggtcttaca gccctcagat gaaactacgg ctctagaaca 841 ggcacaagag tggctggaga aatttgtcag tgggcctcca caagtcatta ggggtttaaa 901 aaaatctgtc tgctctgccc gagaactgta tatagaggag gcgttacaga atgaacgaga 961 cgttttggaa acactgtggg gtggacctgc aaatttagag gctattgcta agaaaggaaa 1021 gcatactaaa tagcctttaa aatgagtgta gtacaggtga agctgcaggg gaacatgcat 1081 ggaggtgaga tgattagaaa tgagctgcgg aagtcattca aaggggactg ctaatctgcg 1141 tagttggctc ggggggcctt ctccatattg taattcagtg ctctgttgtc tttcttatca 1201 tttaacatat accaatttct acattcctgt agtaattctt agcccaggct tatgctttgt 1261 aacatactaa cttttaagag agggtcttaa acttgctatg tagcgccaag ggtagacgtg 1321 aattcctgac actcctgcta ccgcctccca aacacttgtt aatactgctg tttctggctg 1381 ttttggtctt tcttaagtcg aaataattta caaaagcaaa gttaaacaaa atttaaaata 1441 acttaatata tccttcatag gaagcaaaag gcagggagag actagagagg catgtaagaa 1501 atattagtta ttttcgtgtg tgtgttctgt atacatagga tactgatgtg aaatggttct 1561 tcatttaaag aaaaaaaagg cccctctgtc atgggagttt ttgttggcct tttcaaccat 1621 ctgtcttcta tttcaaaaga cctactaaac agtgaaagcc attctactgg ctatacaaag 1681 tagcagagca ttggtctctg agattttcat gttaatagta aagcagtagt attgatttaa 1741 agactcatga agcatccttt tcattttcac cagatttttg agcaatacct aactttttgt 1801 gtggctatct tttaataact aaatttaata gaaacacata acccaaactt tatgtccatt 1861 ccagaattta cttgttccat aaaaactgta taagaattaa cttctaacca gtctcaacaa 1921 gaggtaaaag acactcaaaa taatcacctt tttgttgttt gttttcgcac tctgttaacg 1981 tgataattcg aatacaggga atttagaagt gtgtaaatac aggaccccac tttttaaagg 2041 aaacacaggc agatgtgttt tctccgggac aaattctcaa ttctgtgttc gccagtattt 2101 cctcccttgt caatccatat aaagtgggct tattggttct ataacactat gcttgtagcc 2161 cagacagaaa taccactgat ggagcctggt aaagtaaatg taaataaatg atattagctg 2221 cttgagaaat ttaaatctca cgacctatgg atctttttcc acatttgttt attccaaaca 2281 cagcgcccat tgatagcttc tctttcctta ttctcttctg aagaaatcag acttacttct 2341 tgagtaagga acagtttgaa tagaatgcaa tcaattcaaa cctcaccttt aaaaaagctc 2401 tttagccaca aataccaaag tgtccccatc ccttttccag actcaaacaa attatttctg 2461 ataaactcta gtatttatta aattataaag tttttttaat caaaaagaaa aatgcagact 2521 aagagaaacc tccaagtaca aggacaagac agcaaatctt atggaaggga acaccatgaa 2581 gtgcgttaca gattctgaaa cttattagct gcagctttac atttctatct caagaagacc 2641 aactatagtt gttaatcatc tattttaaaa tcccaaattc acatcaagct tcctgctcat 2701 aatgatatca aatatctcac aggtgccaaa ttttattgaa gattttatac caatccatgc 2761 agaaaaaata agtagtgcaa gagtcagatg aggaccatta atgcacaggg acacactagc 2821 caaaagaact aaaaacttaa aaaaatacac tataaacaga tgtcaagaaa actgtgttat 2881 actgaacagc tctcaactat caacacccca gttcctcaca ttaaataaat ttcagcagag 2941 acatgct

SEQIDNO:35

Amino acid sequence of mouse ECHDCl encoded by the DNA sequence shown in SEQ ID NO: 34. MKRCEVNSKPISEYFGIPCENQEMAKCLLTSSLSVRTKLLQTGVSLYNTSHGFHEEEVKK ILEQFPGGSIDLLKKQNGIGILTLNNPNKMNAFSGVMMLQLLERVIELENWTEGKGLIIH GAKNTFCSGSDLNAVKALSTPESGVALSMFMQNTLTRFMRLPLISVALVQGWAMGGGAEL TTACDFRLMTEESVIRFVHKEMGIVPSWGGTSRLVEIIGSRQALKVLSGTLKLDSKEALN IGLTDEVLQPSDETTALEQAQEWLEKFVSGPPQVIRGLKKSVCSARELYIEEALQNERDV LETLWGGPANLEAIAKKGKHTK

SEQIDNO:36 gi|34853307|ref|XM_341744.1|Rattusnorvegicussimilartouncharacterizedhypothalamus proteinHCDASE(LOC361465),mRNA

1 ggaccgcagt gcaggcgccg cggagcaggt gggctcgtga gattctggag gtctctggag 61 gagctctgag gcgttacaga gaagaaatgg caaaaagtct cttggcttca tctctgtctg

121 taagaacaaa aatcttacaa acaggagtgt cactttataa tacgactcat ggcttccatg

181 aggaagaagt gaagaagata ctggagcagt ttcctggtgg atccattgac ctacagaaga

241 agcagaatgg tattggcatt ctgacgctta acaactcaaa taaaatgaat gctttctcag

301 gtgccatgat gctacaactt ttggaaaggg taattgaatt agaaaattgg acagaaggga 361 aaggcctcat tgttcatgga gcgaaaaata ctttttgctc aggatctgat ctgaatgctg

421 tgaaggcact ctccactcca gagaatggag tggccctgtc tatgttcatg caaaacacct

481 taacaagatt tatgagacta ccattaataa gcgttgctct ggttcaaggc tgggcaatgg 541 gtggaggagc agaacttact acagcatgtg atttcaggtt gatgactgag gaaagtgtga 601 tcagatttgt ccacaaggag atgggtatag ttccaagctg gggtggtgcc agccggctgg 661 ttgaaatcat tggcagcaga caagctctca aagtgttaag tgggacattc aaactggatt 721 ccaaggaagc tttaagaata ggtttggctg atgaggtctt gcagccctca gacgaagcta 781 cggctctgga acaggcacaa gagtggctgg agcagtttgt cagtggacct gcacaagtca 841 taaggggttt gaaaaaatct gtctgctctg gccgggaact gtatctagag gaggcgttac 901 agaacgaaag agatgtttta gaaacactgt ggggtggacc tgcaaattta gaggctattg 961 ctaagaaagg aaaacacact aaatag

SEQIDNO:37 Amino acid sequence of rat ECHDCl encoded by the DNA sequence shown in SEQ ID NO: 36.

MAKSLLASSLSVRTKILQTGVSLYNTTHGFHEEEVKKILEQFPGGSIDLQKKQNGIGILT LNNSNKMNAFSGAMMLQLLERVIELENWTEGKGLIVHGAKNTFCSGSDLNAVKALSTPEN GVALSMFMQNTLTRFMRLPLISVALVQGWAMGGGAELTTACDFRLMTEESVIRFVHKEMG IVPSWGGASRLVEIIGSRQALKVLSGTFKLDSKEALRIGLADEVLQPSDEATALEQAQEW LEQFVSGPAQVIRGLKKSVCSGRELYLEEALQNERDVLETLWGGPANLEAIAKKGKHTK

SEQ ID NO: 38 gi|31542717|reflNM_024693.2| Homo sapiens enoyl Coenzyme A hydratase domain containing 3 (ECHDC3), mRNA i gagtacggac tgggcctggc ctggggcgtc cccgcgaagc ctgggcctgt caggcggttc

61 cgtccgggtc tcggccaccg tcgagttccg tcgagttccg tcccggccct gctcacagca

121 gcgccctcgg agcgcccagc acctgcggcc ggccaggcag cgcgatcctg cggcgtctgg

181 ccatcccgaa tgctatggcc gccgtcgccg tcttgcgggc cttcggggca agtgggccca

241 tgtgtctccg gcgcggcccc tgggcccagc tccccgcccg cttctgcagc cgggacccgg

301 ccggggcggg gcggcgggag tcggagccgc ggcccaccag cgcgcggcag ctggacggca

361 taaggaacat cgtcttgagc aatcccaaga agaggaacac gttgtcactt gcaatgctga

421 aatctctcca aagtgacatt cttcatgacg ctgacagcaa cgatctgaaa gtcattatca

481 tctcggctga ggggcctgtg ttttcttctg ggcatgactt aaaggagctg acagaggagc

541 aaggccgtga ttaccatgcc gaagtatttc agacctgttc caaggtcatg atgcacatcc

601 ggaaccaccc cgtccccgtc attgccatgg tcaatggcct ggccacggct gccggctgtc

661 aactggttgc cagctgcgac attgccgtgg cgagcgacaa gtcctctttt gccactcctg

721 gggtgaacgt cgggctcttc tgttctaccc ctggggttgc cttggcaaga gcagtgccta

781 gaaaggtggc cttggagatg ctctttactg gtgagcccat ttctgcccag gaggccctgc

841 tccacgggct gcttagcaag gtggtgccag aggcggagct gcaggaggag accatgcgga

901 tcgctaggaa gatcgcatcg ctgagccgtc cggtggtatc cctgggcaaa gccaccttct

961 acaagcagct gccccaggac ctggggacag cttactacct cacctcccag gccatggtgg

1021 acaacctggc cctgcgggac gggcaggagg gcatcacggc cttcctccag aagagaaaac

1081 ctgtctggtc acacgagcca gtgtgagtgg aggcagagga gtgaggccca cgggcagcgc

1141 ccaggagccc accttcccct ctggcccagc caccactgcc tctcagctta aacaggtgac

1201 aggctgcttt cgtgacttga tattggtgtc atagcatttg gcctacatta aaagccacaa

1261 tttcatgggg aaaggacaaa atggagggtg actgaggtgc tgacctcaat gcaaggctgg

1321 tgaaccctgc agcgggccag ctatggtggg aagcctggca tttggggtgc tccttgcaac

1381 gtcttaagca agcgaccccc ctgacatagc aaaaggtggc aacccatgga ggcagaaaga

1441 aggacgccag cctgaccctt atctgaaacg tcctaagcag agttaatcct ggctgctcag

1501 gagaggcgac acatttcaaa tctccacgag atattctcca cacagaaaat cttcttgatt

1561 ctatagagac ttaatcatgc ctatggcttt gaataatctt atgtgattta aataaattaa

1621 atctttataa aaaaaaaaaa aaaaaaaa

SEQIDNO:39 Amino acid sequence of human ECHDC3 encoded by the DNA sequence shown in SEQ ID NO: 38.

MAAVAVLRAFGASGPMCLRRGPWAQLPARFCSRDPAGAGRRESEPRPTSARQLDGIRNIV LSNPKKRNTLSLAMLKSLQSDILHDADSNDLKVIIISAEGPVFSSGHDLKELTEEQGRDY HAEVFQTCSKVMMHIRNHPVPVIAMVNGLATAAGCQLVASCDIAVASDKSSFATPGVNVG LFCSTPGVALARAVPRKVALEMLFTGEPISAQEALLHGLLSKVVPEAELQEETMRIARKI ASLSRPVVSLGKATFYKQLPQDLGTAYYLTSQAMVDNLALRDGQEGITAFLQKRKPVWSH EPV

SEQ ID NO: 40 gi|32129265|ref|NM_024208.3| Mus musculus enoyl Coenzyme A hydratase domain containing 3 (Echdc3), mRNA i ggcttgcaca gtcaaccttg cttttcttgg ctgcaatggc tgtggtcgca ggccttcggg

61 cctttggggt gaagtggccc agctggctca ggcgcaaccc atgggcccct ctctccgccg

121 gcttctgcag cccagggtca gcaggacctg cggggtcgga gtcagagcca aggctcacca

181 gcacgcgaca gcaggacgga atcaggaaca ttgtcttaag caatcccagg aggaggaatg

241 cgctgtcact ggccatgctg aaatctctcc gaagtgacat tcttcacgaa gctgaaagtg

301 aagacctgaa agtcattata atttcagccg agggccctgt gttttcatct ggacatgatt

361 tgaaagagct gacagatgca caaggccgtg attatcacgc tgaggtattt cagacctgtt

421 ctgaggtcat gatgctgatc cggaaccacc cggtccccat ccttgccatg gtcaatggct

481 tggccacagc tgcaggctgc cagctcgtgg ccagctgtga tattgctgtg gcaagtgaca

541 agtcttcttt tgcaactcct ggagtgaatg ttggactttt ctgctccacc cccgcggtcg

601 ccctggggag agcagtgccc agaaaggtgg ccctggagat gctctttact ggggagccca

661 tttctgccca ggaggccttg cgccatggcc ttatcagcaa agtggtacca gaggaacagc

721 tggaggcaga gaccatgaga atagcaaaga agatttcctc tttgagccgc tctgtggtgg

781 cgttgggcaa ggccaccttt tacaaacagc tgccacaaga ccttagaacc gcctacttcc

841 tcgcctccca ggccatggta gacaacctgg ccttgcagga tgggcaggaa ggaattgaag

901 ccttcatcca gaagagaaag cccatctggt cacactgagc ccgcatgagg agtgctgagt

961 taatggtcag ccctagctga cccccagccc tcccatctcc tcctctcaac ccaaccatat

1021 actgccacct cttgattgta agagaacatt gccagccttt ctaacttgga tgttggtttc

1081 tcagtgtgtg atctgtattg aatgccatgg ttctgtggga aatgaataca ggggagggaa

1141 cgacttgcta ggtcagtggg caggttaata tgcactgggg tgtgcaggct gtgacagaaa

1201 ccccagtacc caacggagcc tgaagtgagg tgctgcccat acagaggaca gtcaagtgaa

1261 gcgtgaagga agggtgccgc ccccatgctt ctgcagtgtc cttcaggcac agtccgttct

1321 ggttgttcat ggcaagttga acagttcaaa tctccatgag accatctccc cactgaaaaa

1381 tttcttgatt ctaccaggaa atcatcacac ctgtagtttg gaataatctt atgtgatttg

1441 aataaattaa atatttatag agctgggtca tttcatttct aacccaccgc aagctaagaa

1501 aagaaaagag agaatattct ctttgtatgt ccactctgat gggcacaaag caagggcctt

1561 gccctcacta ctaaaccaga ggataaaagc tgcccagaac agggcaagga cccagagcag

1621 accccatcca atgagagtcg cttcctcagg acacagttca gaactgtgct cagcttctgg

1681 taataaaccc agactaaact catatttaga cctagtcata tttttttggc atctggtcta

1741 atgtagccca aagagtgttc aaattttctg tgcctgtaaa cttgaccata aatcaatatc

1801 catctatcct cct

SEQIDNO:41

Amino acid sequence of mouse ECHDC3 encoded by the DNA sequence shown in SEQ ED NO: 40.

MAVVAGLRAFGVKWPSWLRRNPWAPLSAGFCSPGSAGPAGSESEPRLTSTRQQDGIRNIV LSNPRRRNALSLAMLKSLRSDILHEAESEDLKVIIISAEGPVFSSGHDLKELTDAQGRDY HAEVFQTCSEVMMLIRNHPVPILAMVNGLATAΆGCQLVASCDIAVASDKSSFATPGVNVG LFCSTPAVALGRAVPRKVALEMLFTGEPISAQEALRHGLISKVVPEEQLEAETMRIAKKI SSLSRSVVALGKATFYKQLPQDLRTAYFLASQAMVDNLALQDGQEGIEAFIQKRKPIWSH SEQ ID NO: 42

gi|4885386|ref|NM_005327.1| Homo sapiens L-3-hydroxyacyl-Coenzyme A dehydrogenase, short chain (HADHSC)₅ mRNA i cgcccccaga gtctggcttt ccgcggctgc ccgcctcgcg cgtcttccct gcccgggtct

61 cctcgctgtc gccgccgctg ccacaccatg gccttcgtca ccaggcagtt catgcgttcc

121 gtgtcctcct cgtccaccgc ctcggcctcg gccaagaaga taatcgtcaa gcacgtgacg

181 gtcatcggcg gcgggctgat gggcgccggc attgcccagg ttgctgcagc aactggtcac

241 acagtagtgt tggtagacca gacagaggac atcctggcaa aatccaaaaa gggaattgag

301 gaaagcctta ggaaagtggc aaagaagaag tttgcagaaa accctaaggc cggcgatgaa

361 tttgtggaga agaccctgag caccatagcg accagcacgg atgcagcctc cgttgtccac

421 agcacagact tggtggtgga agccatcgtg gagaatctga aggtgaaaaa cgagctcttc

481 aaaaggctgg acaagtttgc tgctgaacat acaatctttg ccagcaacac ttcctccttg

541 catattacaa gcatagctaa tgccaccacc agacaagacc gattcgctgg cctccatttc

601 ttcaacccag tgcctgtcat gaaacttgtg gaggtcatta aaacaccaat gaccagccag

661 aagacatttg aatctttggt agactttagc aaagccctag gaaagcatcc tgtttcttgc

721 aaggacactc ctgggtttat tgtgaaccgc ctcctggttc catacctcat ggaagcaatc

781 aggctgtatg aacgaggtga cgcatccaaa gaagacattg acactgctat gaaattagga

841 gccggttacc ccatgggccc atttgagctt ctagattatg tcggactgga tactacgaag

901 ttcatcgtgg atgggtggca tgaaatggat gcagagaacc cattacatca gcccagccca

961 tccttaaata agctggtagc agagaacaag ttcggcaaga agactggaga aggattttac

1021 aaatacaagt gatgtgcagc ttctccggct ctgagaagaa cacctgagag cgctttccag

1081 ccagtgcccc gagtgcctgt gggaatgctc tttggtcaga cattccctca cacagtacag

1141 tttaataaat gtgcattttg attgtaatct atcgaagtga ttattacacc agttacagca

1201 gtaatagatt ctccattaag aaataattcc cttttttagt ctgttcattt ctgtgtattt

1261 tctaaacagc tttacaccct tggtgccttg gagcaaacat gttttttgaa ccttgtcatt

1321 tttgtgaaga attgcctaga ttccttctct catcaacggg aaagtacttc ctctgagagt

1381 gcgagtgcac catgctcact gttgctgcgt gggagagtca caagccactg gcaagcaagt

1441 ggtatagtct gtgaagcact gcagcgagca gcacctggat cttgccttta taagaacatt

1501 ttactacctg cagctttgag tcttgcccta cattttgggc atgacataag atgtgtcttt

1561 attcagctcg tcgtgaagat gctgctgctg aatgggtcag catatctctg tttgcatggt

1621 ttgcaggagg tcggttttca tggtcattca gttccacaga tctgaatgat tactgtctgt

1681 ctgtgtcttt tttccatgag aaatcactgt tgcaaattgc ctataaattg actctactaa

1741 aataacaatg tttcagtctg aaaatttgaa ttgaaaaaaa tgtataatat aaaattgtaa

1801 tacactcaaa tgattataaa agtaaaagtt ggtaatttag gcaaaaaaaa aaaaaaaaaa

1861 aaaaaaaaaa aaaaaaa

SEQIDNO:43

Amino acid sequence of human HADHSC encoded by the DNA sequence shown in SEQ ID NO: 42.

MAFVTRQFMRSVSSSSTASASAKKIIVKHVTVIGGGLMGAGIAQVAAATGHTWLVDQTE DILAKSKKGIEESLRKVAKKKFAENPKAGDEFVEKTLSTIATSTDAASVVHSTDLVVEAI VENLKVKNELFKRLDKFAAEHTIFASNTSSLHITSIANATTRQDRFAGLHFFNPVPVMKL VEVIKTPMTSQKTFESLVDFSKALGKHPVSCKDTPGFIVNRLLVPYLMEAIRLYERGDAS KEDIDTAMKLGAGYPMGPFELLDYVGLDTTKFIVDGWHEMDAENPLHQPSPSLNKLVAEN KFGKKTGEGFYKYK SEQ ID NO: 44 gi|2078328|gb|AF001903.1|HSAF001903 Human 3-hydroxyacyl-CoA dehydrogenase, isoform 2 mRNA, complete cds

1 cgtgtatacc cgctcaacgc tgggacgtta cagccagggc caatgggcag agcgggactc 61 gaggccccgc ccccgccttg tggcgtcacg gggacgccgg gggcgcgcgg gctgcagggc 121 cgcgtaggtc cccgccccca gagtctggct ttccgcggct gcctgcctcg cgcgtcttcc

181 ctgcccgggt ctcctcgctg tcgccgccgc tgccacacca tggccttcgt caccaggcag

241 ttcatgcgtt ccgtgtcctc ctcgtccacc gcctcggcct cggccaagaa gataatcgtc

301 aagcacgtga cggtcatcgg cggcgggctg atgggcgccg gcattgccca ggttgctgca

361 gcaactggtc acacagtagt gttggtagac cagacagagg acatcctggc aaaatccaaa

421 aagggaattg aggaaagcct taggaaagtg gcaaagaaga agtttgcaga aaaccctaag

481 gccggcgatg aatttgtgga gaagaccctg agcaccatag cgaccagcac ggatgcagcc

541 tccgttgtcc acagcacaga cttggtggtg gaagccatcg tggagaatct gaaggtgaaa

601 aacgagctct tcaaaaggct ggacaagttt gctgctgaac atacaatctt tgccagcaac

661 acttcctcct tgcagattac aagcatagct aatgccacca ccagacaaga ccgattcgct

721 ggcctccatt tcttcaaccc agtgcctgtc atgaaacttg tggaggtcat taaaacacca

781 atgaccagcc agaagacatt tgaatctttg gtagacttta gcaaagccct aggaaagcat

841 cctgtttctt gcaaggacac tcctgggttt attgtgaacc gcctcctggt tccatacctc

901 atggaagcaa tcaggctgta tgaacgagac ttccaaacgt gtggtgattc taactcgggt

961 ttgggctttt ctttaaaagg tgacgcatcc aaagaagaca ttgacactgc tatgaaatta

1021 ggagccggtt accccatggg cccatttgag cttctagatt atgtcggact ggatactacg

1081 aagttcatcg tggatgggtg gcatgaaatg gatgcagaga acccattaca tcagcccagc

1141 ccatccttaa ataagctggt agcagagaac aagttcggca agaagactgg agaaggattt

1201 tacaaataca agtgatgtgc agcttctccg gctctgagaa gaacacctga gagcgctttc

1261 cagccagtgc cccgagtgcc tgtgggaatg ctctttggtc agacattccc tcacacagta

1321 cagtttaata aatgtgcatt ttgattgtaa tctatcgaag tgattattac accagttaca

1381 gcagtaatag attctccatt aagaaataat tccctttttt agtctgttca tttctgtgta

1441 ttttctaaac agctttacac ccttggtgcc ttggagcaaa catgtttttt gaaccttgtc

1501 atttttgtga agaattgcct agattccttc tctcatcaac gggaaagtac ttcctctgag

1561 agtgcgagtg caccatgctc actgttgctg cgtgggagag tcacaagcca ctggcaagca

1621 agtggtatag tctgtgaagc actgcagcga gcagcacctg gatcttgcct ttataagaac

1681 attttactac ctgcagcttt gagtcttgcc ctacatttt

SEQ ID NO: 45

Amino acid sequence of human HADHSC variant ORF number 1 encoded by the DNA sequence shown in SEQ ID NO: 44.

MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLAFRGCLPRASSLPGSPRCRRRCHTM AFVTRQFMRSVSSSSTASASAKKIIVKHVTVIGGGLMGAGIAQVAAATGHTWLVDQTED ILAKSKKGIEESLRKVAKKKFAENPKAGDEFVEKTLSTIATSTDAΆSWHSTDLVVEAIV ENLKVKNELFKRLDKFAAEHTIFASNTSSLQITSIANATTRQDRFAGLHFFNPVPVMKLV EVIKTPMTSQKTFESLVDFSKALGKHPVSCKDTPGFIVNRLLVPYLMEAIRLYERDFQTC GDSNSGLGFSLKGDASKEDIDTAMKLGAGYPMGPFELLDYVGLDTTKFIVDGWHEMDAEN PLHQPSPSLNKLVAENKFGKKTGEGFYKYK

SEQIDNO:46 gi|14150815|gb|AF375596.1|AF375596Sl Mus musculus medium and short chain L-3- hydroxyacyl-Coenzyme A dehydrogenase (Mschad) gene, exon 1 ; nuclear gene for mitochondrial product

1 aagcttgtaa gtggctttac cactcaaaac cctggcttcc tcacccttag aggataacat

61 gaaagcccga gaactgccct gtgaccaaac agctctagaa cctgagcctt gaaaacacac

121 acattccaat tccaacactt tctgtccaat cccggctacg tttctttatc tgggcttcag 181 tttccctgtg tattaaagaa ggctactgcc cagacccttt gttctccagg ttgggagcag 241 ctggatgggt tccccgggag gaggtgtccc cgctgcacgt ggaggggaaa ggattgtccc 301 caggcttctg accctcagtt ctcaccttta gagttccctg agccccaccg ccccacttgg 361 gcagctccgt gcgggctttc ccgcctctct ttctacatcg tggcctctcg ggtctccagg 421 aagaggaagg gtaaagactg acaccagggg ttagagagac cacgtctact tccaggcgct 481 cttatttggg cctgaaccca cagcgcctga cgcaggtcgc agaggacatc ctcagacctt 541 gggcgcatgg tcccggcaca acctttcttc gtgaggaccc cagagcccta gaagggagaa 601 tgggacattg tatgtagcgc ccaggagtct gattgcaaac gaacgccctc tccaccccac 661 cctaggcggc gccacccttg tcgcccctct gctgcgtgtg accccaaggg cttgggcgat 721 tgtgtctccc tgagtacagt taaaattgtg ttcggcttaa aaaaaaaaaa aaaaaaaaag 781 aaggctacct cgtgggatta ccataaatat tccataactt aactcaccca aaacacctag 841 aacaatggca aacatcctga acggctgaat gtgtgttggc tgcttccatg tgcaaccatt 901 taacacgagc aagtcaagtg ccatcaagat ggtggagagg gaaaagactc tcgttaccaa 961 acctaatgac ctgggagccc acaggataga aggagaaacc catcttctgt aagttgccgt 1021 gtggccttca tgcgtgactc gtggtatgta agcacacaca agataaatgt tgaagatcaa 1081 aagtaaataa aagttgctca gaaaggtgac tcccttcgtc gctcttcttc aggaggctga 1141 gcgaatgact cgctttcaaa gcacaaaggt ttgtccacgg gaatctaagg aaaacaaatc 1201 cagagtttca tttgtaaaga tgtagtgcat agctgttccc tccttggggg gaatgggggg 1261 tggggtgggg gaggagtttg cactgcacca ccctccccac tggcctactt ggtaattctt 1321 ttcttttatc ttgacaaatg gtttagagaa agtcagctga gagcagtcca ctggcaacag 1381 ctcagagggc ccacctatga gctatgaaac gggaaaatcc tgatctataa atcccacagc 1441 cacgagggca caggtgagat atgcgaaggc ttcgaacctt taatccagac tgtaccaacc 1501 ctaccacgca ccactgtatt tcctgtaaat tcacctttaa ggttttgttt tgttttgaat 1561 taaaccactt tgttcccaag agatcttatg ttttaggttt cctaaacgtt aacttgtgag 1621 ttggagccat tgtgcttctg ggtagagaga aaggtttccc aggtgattaa agcgcagctg 1681 gcttagggac aacagcagac aggataagaa aacctgcaat aagaaacctt cataatctga 1741 agtcagccgt gacccttttc ctccaaaagc tcaaactgat aaaattattt gtaaaaatag 1801 cccaagtgtt attcaaacgc tcggctcggc tgtcatttgg aggatggtct cagtgggctg 1861 tgtgaaaaga gaactctgct ttctcaaact taccacattt cttaattatg aaaattaatt 1921 tattttcatg aaaccttagg caaggtcaac catcatggat tcttcagtaa gtgaaccttc 1981 agctcgatgt tctctgggtt ttgctcttgg aatcacaact ttttgttttc tgatggtctt 2041 agggttttac ggcagtgaac agacaccatg accaggcaat tcttataaag gaaaacattt 2101 aattggggct gccttacagg ttcagaggtt ccctccatta tcatcaaggt gggagcatgg 2161 catcatccag gcaggcatgg tgcaggagga gctgagagtt ctacatcttc atctgaaggc 2221 tgctagtgga agacttccag gcagctagga tgagggtctt aagcccatgc ccacagtgac 2281 ataacaactc caacaaggcc acacctccta atagtgccac tccttgggcc aagcatatac 2341 acaccatcac actgatatag gaaagctaaa acctattcaa caaaacaaga aagacagtat 2401 cattctcatt cattccccca aagccagagg tcattctctt tccataaaga aacaaacaaa 2461 aaattacaac atactcaatg aatttgaccc cctgatcaat gcttttggct gttaccaaat 252,1 cctgcccttc tgtatatgtg cagagggaag gctgtcggcc cagctttctc tgcctggtca 2581 ccaccatcac catgggtcac agggtctact agtgcctgct ttgatattct tagagcccac 2641 tggctgcggt gtcaaatatg ctgcttttgt gtatggggca tatgtgtggg tatgggggca 2701 tatgtgtggg tatgcccatg caatgtgtaa gcaggcacat tcaagagtac acacgtgggg 2761 gccacgggtt aatgcagaat ggttacctct tgcgcgcacc cgactggcca gcaagaatga 2821 cgctgcaaca ggatctttct gcacacggtt attgggagag cttgattgca gaggcgaaga 2881 gaccccaagc ccagaactgg tgctgcttat ataggcctag gagaggcgtg tctcacaccc 2941 ggattggtaa tgcatgggtt atgcttacca cctcatttgc atgtctcatg cctgattggt 3001 taatgtctct ctcatctgat tggttaactt gtctctcatc tgattggtta acttgtctct 3061 catctgactg gttaacttgt ctctcatctg attggttaat tctcaaaacc tcatcttggc 3121 aaaaaaactt tactgcctat gtatgcatgg tggccagcga tagccagtgc caccctgcaa 3181 cggcacatgt ggctttccac agttacccct gccactctat cctctctgct ttcttcagga 3241 tacagtctct cactgaagct ggagcatacc gattggctac actggctgcc accaagcccc 3301 tgggattgtc ctttcactgc cttccctggg ctaggatcag aggcacaaac tgtcagagcc 3361 agatttttac ataggtgcct ttttacatag gtgccaggga tctgacctca gggtctcctt 3421 gctctcatag caaacaaaca cttacccccc agcacctccc cagcctcaaa ccatgctgct 3481 ctgccttctg tgttctaagt actacagtta tccatctatg tgacccacag agactgcact 3541 gttatctacc tattgctctg taccaggccc ttccttcagt aaagcaacca ggaccctggc 3601 tctgcagctg gccttcGctg tgttttattg gggtgttggt ttttttttta aacagagtct 3661 tgccatgtag cccaggctgg ccttgtactc acagtccacc cgcctctttt ctttacacag 3721 cacccttgtt tatcacagat ggccttggat ttgagagtca ctagggagta ctacagtagt 3781 gtttgtgggt cctcttcaga tgcatacact aaaacccaat gtagaagtgt ttagggatgg 3841 gcctttggga ggtgattggg tggctagtgg cttaagaaag agccccagat ggttctcttt 3901 agagcagtgg ttctcagcct tcctaatgct gtgacccttt aatacagttc ctcgtgttgt 3961 agtgaccccc taaccataaa attattttat tgctttataa ctgtagtttt gctgcggtta 4021 tgagttgtaa gtattttggg agagggaggt ttgccacagg ttgagaacac tgttctagaa 4081 ggagggctgt cagggtaatg ttcgttatga gatgtgactt aatagacttg cttacacaag 4141 cggggctgga gtgtccatca gtggtgcctg ccactggaca ggctgaggct gtcacagcca 4201 ctcagtctgc gaggctggtt gcatcagcag tcccagtctg gctgaaggcc tggaggagcc 4261 ctagagagcc tgcacttcat cccatgttgg aaggcctaag ttaggtgctc atgtcaggga 4321 aggatgactg cagcagctac agcagaatag aggaattctc cagcaggaga agaaggcagg 4381 caggcaggaa gtctattttt ctctctcaga tcactttata tctagggtgc accccacccc 4441 cactctgtat aaggtgctgc ccactcaggg aggacatctt ctcccctcag ttaacctttc 4501 ttggaaatac ctccatggag tcttccagag gtggctctct tagtcggcta cagattcatt 4561 ccatttgaca atcaatattc accatcacac ccttcaaccg tctgcagata caaggaacta 4621 tccttgagct aaaagtgggt cgacatcaga aaatgaacct gatggcacct tgacttgggt 4681 ttgccttgct cccaggagac atttgggggt tttgttgtag cagcacaagt ggatcaagac 4741 ccatttatca ttctttccca aggaaaagca gagatctgaa aacgtacatt accttgggtg 4801 tgaggtacac atgaaatatt acaacagaga tatcatttga gaatatatca tagggctgga 4861 gagatggctc tgtggttaag agcgctgact gctctttcag aggactgggc ttgattctca 4921 gcaccacatg atggctcaca acatctctaa ctccagctca ggaactgatg ccttctctgg 4981 ctcctcggac gtacatccat acagtgcaca gatatacctg gtgagaagaa gaacagaagg 5041 atgagaagaa agaggaggag gaggaggagg aggaggagga ggagggagga ggaggaggag 5101 gaggaggagg agaagaagaa gaaaagaaaa gggagagaag aagaagaaaa tttgttcaca 5161 gcaccagact ggatatattc atcttccaga gaccagtgag agtgcaccct ctcatcaagc 5221 ctctggaaat gtgcttctct ctcagtgcaa ctcagccana gggcctttct ntcttctgca 5281 tcttctcaga ctgctgtaca cattccttcc ttccttcata aacgtgttca ttcttcaagc 5341 tgtgggtttc tgtgggtagc cttctacctc cgttcctant atcttttatt ttattttatt 5401 tttgtgactt ggctggaatg tagcactcag taggctttgc ttattttgaa gaattaaata 5461 taaaaataag attcaaaggg tcaatgcaan acatagcccc tgcttcaaag ggagtgcagg 5521 agagtctctt cccagccaca tgcaagagcc cgaggcaggg aacaggcatg gaaacaattc 5581 tgaaggacaa gnttcactgc tgacagagtt acataaactt tttataggct acagagcgag 5641 gaggttcata aagccatcgg cttacagaac attgctgaag accctgggca ggcaggttac 5701 agtggaacaa gtaattcttt tcctagggtt ttatgccggt gtttgtttgt ttgtttttgt 5761 tgttgttgtt attgttgttg ttgttttaac tgttttagtt tgggacggat gggagcaagt 5821 gttctgctag gcaacacatt gcttaagttc gatgtaacct aagttagata cagaggtggg 5881 taactagaaa cagcccgaga gaacttggac tcgagctcta acattcagac aggaagttag 5941 ttttattctg cagaatgtga gacacagatg agacttttgc agggagcttc attgcacaca 6001 ggattaacta tcatttcttc cagtggggtg aaaggcggat ggctttcctc tggacggtga 6061 gtttggggca ccagatgaac gcttagaagt aaaaccagca gtaatttatg ttatcantag 6121 cacagtagta ggcagaaagg ttggccaata gccaggcttt cccttcctgt gttctctatc 6181 cggggttacc gtcctcattc taaacacaat tctcacgatc acaactccag cccaccagat 6241 tgtgaaggca actacaggtt gtctcttggt gggtccctgc tttgccggag tccatgctgg 6301 cctgagtcct ggcaccgccc tctggggggg ggggcggggt ggacctgcag cttgtgcagg 6361 aggcgggtgg gtggggcgtg ttcgaggccc cgcccccaac gtcgccgacc ccgcccacga 6421 cgctccggga cctctcgcgc tgtccccact gctcctcctc ggctgctgca ctgagctatg 6481 gcgttcgtga ccaggcaatt cttgcgctcc atgtcctcct cttcctctgc gtcggcggcc 6541 gccaagaaga tcctgatcaa gcatgtgacc gtcatcggcg gcgggctgat gggcgccggc 6601 atcgcgcagg tgagcgggcc tcgcgccccg ggtgtggtgg aaatagtttg atgaagtccg 6661 agaaggtgca gcatgcttca gtgtcccaga actacagcct tcggcccgat ccttacgtgc 6721 atgcttctca actaactgcc gggccgggga aggctcggtg gagcgcgctg gtgcacgcgt 6781 gcacactgga gctgaactgt gcacagttgt gcgtgcaaag ttgcagagtg tttgctcact 6841 gcctggatct gacaggaatc cgctcgccaa ganctgggct gcggtttctt ttagttttcc 6901 tgataagttt tttctttgtt ctttctttct tttttccttt acagttcttt gggtgttggt 6961 ctgggcactt tttctttcca agtgtcctgc ctctcccaca agtttccttc cgttgggcct 7021 cacttttgtt acagtttgga aagttcacct acctgggatt tgtggaattg ctgggactcc 7081 cgcccagcct gggccaggaa acttggacct tggacccagt gcccggtgct gaattngggg 7141 tgcttgtcca ggctctgacc tcgagagagn ggcgacagag ataagcatag tttatgctct 7201 ggagaacgtc tctcaatctc tgatcggctt ctgtgggact ttgcctggtg ccagctgagg 7261 cacagttcaa aatcaactgt gcagtttggc tacctgcgat gttctgtagt accattttct 7321 tcttaagagt taacttcgta cacacagtag agagctctga tctttttcca tgaacttgct 7381 attatattcg tatcttttga ggcctttgca gtttgagtgt tgtggcagtg aagggcttac 7441 ctaattttaa ttagggaggg tattcgcagg tcagtgtctt ttcccaacca aatgcacact 7501 tgcatgcttg ctatttatta gccttgactg cacttccttc caaagtccat taaattaaac 7561 aacaaaaacc atacatggct atgctggaga aaatatagct agtctgctgt atccctctgc 7621 accacaaaaa ctcaaggctg tggagggaat gaggattggt tntccagtcc aagaaaaaca 7681 atgtatccct taaacaatnt ttaagcaaca tcttattaac aagataatag ggttctcctc 7741 ccctcccccc aaactgcttt gggattcgaa actattagaa agcatctagc agcttttgca 7801 caaatgcagg atgctgtgtc ttgtggatgc tgtgtctatc caaagaaagt gtgttgaagc 7861 acgggaagca cttagaatta actgggtaag gtgctcgaac tttgacctga gacgagtgga 7921 ttaaagtgat tgacaaggat gggcatcagg gatttgtgga ttaaatactc gagcagctgg 7981 atcagggagt tcctatggaa atgtaagcgg ggagaggaaa agctatgcaa ctcctagcag 8041 aactttttga ataaaagtgt aacaaacacc caccatctaa atagtgggca ttcataagga 8101 acagccattg cctctgggtc actttaggtg accattctga tcctgcaggg gaaactgctt 8161 tcctgattaa tagctctact atgttccagt ggtttagatg gtccatttct tatacttggc 8221 cttgcagcaa acagttctag ttagtgctgt ctccttcctt ccttccttcc ttccttcctt 8281 ccttccttct ttctttcctt tctttccttc ctttcttctt tccttcctcc ctcttccttc 8341 ctttcttcct tcctttcttt ctttcttttc tttctttctt tctttctttc tttctttctt 8401 tctttctttc ttccttcctt tcttaaaatt ggaactcagt tatagttgca gacagttgtg 8461 agctgccatg tgagaactgg gacttgaacc cagatcttct ggaagaggag ccaatgctct 8521 taactgctga gttatctctc cacccatcat gccgtctcct tttgaaaaaa aaatccataa 8581 tggacagttt ttggttcagg gtagtaaatc ttttttttgc ctctggtaca gggatgagtg 8641 atgaattcat gtgctgagcg caggcagttg ggcgatctgc atgttggtga aacagtaaag 8701 cagttgcttg gtctctgcag tttctctaga gcagagggtc tgtaggaata tggaaaagca 8761 ataaaggaat taactgacac acacatagca tatagctcca agaagccaga agtgtcattg 8821 tgatcattgg caccattgct gccatctgtc ctcttgtcct tttagcctca ggcccctctt 8881 tgttcctgat ctccatgttg aggcaggagc cttgggttta ggtaggaaat atcttgctta 8941 accctgacac agatccagct gacagacagt gcagtttgct cacgagctgc tgagaaggac 9001 agcacctttt atttaattat tccacccaag tgaagccata aaagtacaaa ctcgaagtag 9061 catcagggtt accctgcatc acacattcag ctgcatttct tctgaactct atgaaatggt 9121 ctaagtcagt ggagagtctg tttgtagttt taactaatcg gcgtgttcca tttngtgctg 9181 agtgggatgg aaaggggtgt aatacatttg tacgcaccca atgcatttta tcaaatagtt 9241 aagtaattta gacaatgagg tcagggttag ttacatttag ccagagtata ggccatagtg 9301 atgtgtactt ctaagagtgt ctacattgcc tgcccttttt tgtttgtttt aaattaaaaa 9361 aaaaaacaaa aacccaaacc aaacctctta gcctgcaggt taatgtttaa gagcaatgac 9421 ttgttttatg tgtttgcctg tggctctcac tgctgatttc tcttgaggca aaatggcttg 9481 tatcattaaa tgaactttga gtggagacag atcgcttttt gctttgtaga gagagaaaga 9541 ggaagctgca agctgtgtgc ttctcaggtt gatagaagag ttctaagcac ggcttagccc 9601 actgtctttg taagaattgt ccagagcgct catacacttc attacatgac ttgtgtgcag 9661 ccactggcca accaggaata aggtttgaga gactttctgg cacaatgtgg tctacatctc 9721 acacttttgg gggtgtggag aatatttgaa cttgtgaaga tcaggagtaa gttcatctga 9781 ccaaagccac caaacgtgtg tggtttgtgt gcctgtgtgt atgtgtgttt gaacatgtgt 9841 gtccttttca aaacgcaaag gatgtgctgg ctagtcccag ctctcttaca tggagatggg 9901 aggtgatgac agcagagtca cctagaagct agaagaccag ccagcctgga gtatgtatca 9961 tggcagaagc cacaagagag accctgcctc atggtaggag agaaccaact cccatacgtt 10021 atcctttgct cttctcatgc acgtgtacac acacacacac acctgttcta aatagtgtct 10081 attctttaga gctc

SEQIDNO:47

Amino acid sequence of mouse HADHSC encoded by the DNA sequence shown in SEQ ID NO: 46. MAFVTRQFLRSMSSSSSASAAAKKILIKHVTVIGGGLMGAGIAQVAAATGHTVVLVDQTE DILAKSKKGIEESLKRMAKKKFTENPKAGDEFVEKTLSCLSTSTDAASVVHSTDLVVEAI VENLKLKNELFQRLDKFAAEHTIFASNTSSLQITNIANATTRQDRFAGLHFFNPVPMMKL VEVIKTPMTSQKTFESLVDFCKTLGKHPVSCKDTPGFIVNRLLVPYLIEAVRLHERGDAS KEDIDTAMKLGAGYPMGPFELLDYVGLDTTKFILDGWHEMEPENPLFQPSPSMNNLVAQK KLGKKTGEGFYKYK SEQ ID NO: 48 gi|17105335|ref|NM_057186.1| Rattus norvegicus L-3-hydroxyacyl-Coenzyme A dehydrogenase, short chain (Hadhsc), mRNA

1 tgctggttct cggctgctcc actgagctat ggcgttcgtg accaggcaat tcgtgcgctc 61 catgtcctcc tcttcctctg cgtcggcggc cgccaagaag atcctgatca agcatgtgac

121 ggtcatcggc ggcgggctga tgggcgccgg catcgcgcag gtagctgcag caactggcca

181 tacagtagtg ttggtggacc aaacagagga catcctggca aaatccaaga agggaattga 241 agagagcctt aagagaatgg caaagaagaa gttcacagaa aaccctaagg ctgccgatga

301 gtttgtggag aaaaccctga gctccctttc aaccagcacc gatgccgcgt ccgtggtgca

361 cagcacagac ctggtggtgg aggccattgt ggagaacctg aagttgaaga atgagctatt

421 ccagaggctg gacaagtttg ctgcagaaca caccatcttt gccagcaaca cgtcttcttt

481 gcagatcaca aacatagcca atgccaccac cagacaagac cgatttgctg gcctccactt

541 ttttaacccc gtccccatga tgaagcttgt ggaggtcatt aaaacaccga tgaccagcca

601 gaagacattt gaatctctgg ttgacttttg taaaacctta gggaagcatc ctgtttcctg

661 caaggacact cctggattta tcgtgaaccg tctcttggtg ccatacctca tagaagctat

721 ccggctgcat gagcgaggcg atgcatctaa ggaagacatc gacaccgcaa tgaagctggg

781 agccgggtat cccatgggtc cctttgagct tcttgactat gttggactgg atactacaaa

841 gttcatctta gacgggtggc acgaaatgga tccggagaac cccttatttc agcccagtcc

901 ttccatgaat aatttggtgg cccagaagaa gctgggcaaa aagaccggag aaggatttta

961 caaatacaag tgatcccccc tcggcagcat ctccagccag ccactggaca aggacaagca

1021 cgctctgcac tgttgtttcc aggcttgccg tgggctgctc agtggacccc cccttgcagt

1081 ctctctgacg taatctcttg gctagttacg gtaatggggt tcttccactg atatctaatt

1141 ctctagttta gtctgttctc tgtgaatttt tctgaaaagc agtataccct gggtgccttg

1201 gagcaaacat ctttttctct ggaccttgcc actttttgta agaagcaatc attagccgca

1261 ttcactcagg tctcctgaaa atgagtatgc cgtgtttatc agcgttgaac cccaggggca

1321 ggcaccatgg tgcctacaga tgcacctgag aggccttgcg tgcctgggaa catttgtagc

1381 ccgcagcctc gagccttagc ctacattctg ggcgtgacag aaaatgtccc gtctttttta

1441 ctcctcatca ggacaggact cctggagttt tgggcaagta cctgtgagct tggttcttgg

1501 cccatcttcg tggccgttcg gatcttaacc gtcactgtct gtctctctca tttcttcagg

1561 agaaatcagt gctacaaagt gcctctgagc tgactctact aaaatgcagt cttttaatct

1621 gtaaacattg ggatgggaat aaataaacgt atacgacttg SEQIDNO:49

Amino acid sequence of rat HADHSC encoded by the DNA sequence shown in SEQ ID NO: 48.

MAFVTRQFVRSMSSSSSASAAAKKILIKHVTVIGGGLMGAGIAQVAAATGHTVVLVDQTE DILAKSKKGIEESLKRMAKKKFTENPKAADEFVEKTLSSLSTSTDAASVVHSTDLWEAI VENLKLKNELFQRLDKFAAEHTIFASNTSSLQITNIANATTRQDRFAGLHFFNPVPMMKL VEVIKTPMTSQKTFESLVDFCKTLGKHPVSCKDTPGFIVNRLLVPYLIEAIRLHERGDAS KEDIDTAMKLGAGYPMGPFELLDYVGLDTTKFILDGWHEMDPENPLFQPSPSMNNLVAQK KLGKKTGEGFYKYK

SEQ ID NO: 50 mbx|235496 Homo sapiens Metabolex clone; similar to gi:37181941 i gcaagtccaa acaggcttcg cccacattcc ctggctgctc tccagcccgc agcagagaca

61 acaaagttca gtgactgaga gggctgagcg gaggctgctg aaggggagaa aggagtgagg 121 agctgctggg cagagaggga ctgtccggct cccagatgct gggcctcctg gggagcacag 181 ccctcgtggg atggatcaca ggtgctgctg tggcggtcct gctgctgctg ctgctgctgg 241 ccacctgcct tttccacgga cggcaggact gtgacgtgga gaggaaccgt acagctgcag 301 ggggaaaccg agtccgccgg gcccagcctt ggcccttccg gcggcggggc cacctgggaa 361 tctttcacca tcaccgtcat cctggccacg tatctcatgt gccgaatgtg ggcctccacc 421 accaccacca cccccgccac acccctcacc acctccacca ccaccaccac ccccaccgcc 481 accatccccg ccacgctcgc tgaggctgct gtcgccggtg cctgtggaca gcagctgccc 541 ctgccctccc atctgttccc aggacaagtg gaccccatgt ttccatgtgg aaggatgcat 601 ctctggggtg aacgagggga acaatagact ggggcttgct ccagctgcat ttgcatggca 661 tgccccagtg tactatggca gcagagaatg gaggaacact gggtctgcag tgctgaaggg 721 tttggggagt ggagagcaag ggtgctcttt cggggctgga cagcccgtct tgtgacagtg 781 actcccagtg agccccagaa atgacaagcg tgtcttggca gagccagcac acaagtggat 841 gtgaagtgcc cgtcttgacc tcctcatcag gctgctgcag gcctctggcg ggcagggcac 901 tgggagaggc cctgagaatg tccttttggt ttggagaagg cagtgtgagg ctgcacagtc 961 aattcatcgg tgccttagtc caagaaaata aaaaccacta agaagctttt gtgaaaaaaa 1021 aaaaaaaaaa SEQ ID NO: 51

Amino acid sequence of human LGLL338 encoded by the DNA sequence shown in SEQ ID NO: 50.

MLGLLGSTALVGWITGAAVAVLLLLLLLATCLFHGRQDCDVERNRTAAGGNRVRRAQPWP FRRRGHLGIFHHHRHPGHVSHVPNVGLHHHHHPRHTPHHLHHHHHPHRHHPRHAR

SEQ ID NO: 52 gi|12852267|dbj|AK014425.1| Mus musculus 18 days pregnant adult female placenta and extra embryonic tissue cDNA, RIKEN full-length enriched library, clone:3830408D24 producthypothetical Histidine-rich region containing protein, full insert sequence i gctctggctg ttgagaagcc tgtccaaaca gacctctccc aaattccctg gctgttctcc

61 agtctgcagg agccgagaca cccttgagtt cagtgactgt gagggctgag cagaggctgc

121 tgaagggagc cactgagtga agtgcagaga tcctctggct tccacatgtt aggccttctg

181 gggaacacga cccttgtgtg ctggatcacg ggcacagcac tggcgttttt gatgttgctg

241 tggctgatgg ccctctgcct tttccacaga tcacaggagc atgacgtgga gagaaaccga

301 gtccgacaag cccggcctcg actcttccat ggggggcgcc tgcgtctccc aagacttgtt

361 caccatcacc accatcacca tgtgaccggg gtgaccagtg tgggcgttca ccaccaccat

421 caccattctc cccatcgtct ccaccaccac aagcaccacc accgccacca ccatgctcat

481 ggagcccgcc gctgaggcca atagatagca tctacctggc tctgccctcc atcagcagca

541 acatgagtcg atcctgatgc tgccacggaa aaggatgtgc ctctgggatg aaggggggta

601 ctgggaccct ggtcctgctt gggtttcatt tgcatatgag cccttctccc tatgtgcaac

661 agagacccac ctgggtggcc ctctacacaa tgtggggctt gagcttcgag cagagctggc

721 tgagtttcct accttgtgac tgcaactcct ggtgaccctg gaagtaacaa gggtatctgg

781 cagaaccaga gcccaggtgg agatggagag ttcttctgat tggggaggcc ctgtgatgag

841 cttccagggg cagactgtgg tacgggcatt cactgctgct tggctgtaag aaataaaagc

901 caccaggaag ctttttgtgt gaactggttc ttgactgtgg cacagtggga gggagggagt

961 catgagggcc ctgggaactc ttctggaagg agctgagcct ggggtctgga acagagagaa

1021 gtaggtggtc cccgcctaag ctctgaggaa gaattcagtg tggacggccc agagctttgg

1081 agaagggaca gttgagaccc ctagcctggg ttctagctct cggagcaccc tgcctgagtg

1141 ctcctcctag cctggtccag agcaggaacc aaccctgggt tcagtgtctg tttggggact

1201 gaatagggat tcttatgcag actctgagtc tccagccagc ctgtctgcag atgcacagta

1261 gcagctgata agaccagagg gagggaacag ttaactgctt ggcatgccgg gtggcctcaa

1321 gagaatgtgc ctggcctgag cctcagtttt tccttcctta aaatggaatg gatagtagag

1381 actcctacca cagtcaacag gcatgcaaag gacccacaca cactatgaat aaaaggttgg

1441 gt SEQIDNO: 53

Amino acid sequence of mouse LGLL338 encoded by the DNA sequence shown in SEQ ID NO: 52.

MLGLLGNTTLVCWITGTALAFLMLLWLMALCLFHRSQEHDVERNRVRQARPRLFHGGRLR LPRLVHHHHHHHVTGVTSVGVHHHHHHSPHRLHHHKHHHRHHHAHGARR SEQ ID NO: 54

235496 Rattus norvegicus computational transcript prediction from genomic (RGSC 3.1)

1 tctggctgtt gagaagcccg tccaaacagg cctctcccac attccctggc tgttctccag

61 tctgcaggag ctgagacacc cttgagttca gtgactgtga gtcctgagca gaggctgctg

121 acgggggcca ctgagtgaag tgtggagaac ctctggcttc cagatgttag gccttctggg

181 gaacacaacc cttgtgtgtt ggatcacagg cactgtgctg gcttttttga tgttgctgct 241 gatgctggcc ctctgtcttt tccacaggtc acaggaacat gatgtggaga gaaaccgaat

301 ccgacaagcc cggcctagac tcttctacgg ccggcgtctg cgtctcccaa gagtcgttca

361 ccatcaccat caccgtggcc cacatggggt gaccagtgta ggcgttcacc agcaccatca

421 ttctccccat cgtctccacc agcaccgtca ccaccaccac cacggtcatg gagcccgccg

481 ctgaggccaa tagatagcac ctactgactt tgccctccac ccagcagcaa aatgagtgga

541 tcctgatgct tccatagcaa agggtgtatc tctgggatgg atgaggatac tgggatcctg

601 gtcctgcttg ggtttcattt gcatacgagc ccttcttcct gtgcatgaca aagacctgag

661 aaccccctga ttggccctct gcacaatgga gggcttgagc ttggagcagg gctggttgaa

721 cttcctacct tgtgactgcc actcctggtg accctggaag cctgggtgga tatggagtgc

781 tctggttggg ggggctctgt gacatgcttc caggggcaga atgtggtctg ggcattctca

841 gctgcttggc tgtaagaaat aaaagccact agaaagcttt ttttgtgaaa ctggttcttg

901 actgttggag ggagggaggg ttgtgtcacg gggccctggg aactcttctg gaaggagaag

961 ctgaggtggg gtctggctgt ggaacgggga gaagcaggca gtccctacgt aagctctgag

1021 aaagaattca gtgtggacag cctagagctt tgggaaaggg cctgctgaga ccacctagac

1081 tgtgtcctag ctctcggagc actctactga gtgctctacc tcgcctggtc cagagcaggt

1141 accaacactg ggttcagcgg ctggggactg agtagggatt cttatcccac ccttgagttt

1201 ccagccagcc tgtttgcgtt tgcagatgta aggtagtggc ccgataagac cagagataag

1261 gaacaattaa ctgcttggca caccaggcag cctcaggagg atgtgcctgg cctaggcctc

1321 agtttcttcc tccttaaaat ggaatagtag agactccttc cccagtcaac aggcatgcaa

1381 atgaccctaa cacactatga ataaacggtt gggtcatcag cagcaacat

SEQIDNO: 55

Amino acid sequence of rat LGLL338 encoded by the DNA sequence shown in SEQ ID NO: 54.

MLGLLGNTTLVCWITGTVLAFLMLLLMLALCLFHRSQEHDVERNRIRQARPRLFYGRRLR LPRVVHHHHHRGPHGVTSVGVHQHHHSPHRLHQHRHHHHHGHGARR

SEQIDNO: 56 gi|13386481|re^NM_030572.1|HomosapienshypotheticalproteinMGC10946(MGC10946), mRNA

1 ctgacaagat gtccctgtgg actcccaaac tctactccag atggggaggt gcccttaaca 61 ccaagatttt aaaagctcca atttcagagc aagagtcgaa aactcacaga taaagttata

121 gttatttcag ggttctgaaa agacgcagaa catgaaggga ctcagaagtc tggcagcaac

181 aaccttggct cttttcctgg tgtttgtttt cctgggaaac tccagctgcg ctccgcagag

241 actgttggag agaaggaact ggactcctca agctatgctc tacctgaaag gggcacaggg

301 tcgccgcttc atctccgacc agagccggag aaaggacctc tccgaccggc cactgccgga 361 aagacgaagc ccaaatcccc aactactaac tattccggag gcagcaacca tcttactggc

421 gtcccttcag aaatcaccag aagatgaaga aaaaaacttt gatcaaacca gattcctgga

481 agacagtctg cttaactggt gaaaatatac tggattatgt ttaattatgg ttctattctc

541 tttgaaaaca tgaaccatgt gaataaaacc tttggaccct ttttaaaaaa aaaaaaaaaa

601 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa SEQIDNO: 57

Amino acid sequence of human MGC 10946 encoded by the DNA sequence shown in SEQ ID NO: 56.

MKGLRSLAATTLALFLVFVFLGNSSCAPQRLLERRNWTPQAMLYLKGAQGRRFISDQSRR KDLSDRPLPERRSPNPQLLTIPEAATILLASLQKSPEDEEKNFDQTRFLEDSLLNW SEQIDNO: 58 Amino acid sequence of human MGC 10946, a soluble active secreted form derived from SEQ ID NO:57.

APQRLLERRNWTPQAMLYLKGAQGRRFISDQSRRKDLSDRPLPERRSPNPQLLTIPEAAT ILLASLQKSPEDEEKNFDQTRFLEDSLLNW SEQ ID NO: 59

genomic|mouse computational transcript prediction from genomic

1 atgaaggggc ccagcgtcct ggcagtgaca gccgtggtcc ttctcctggt gctgtctgcg

61 ctggaaaact ccagcggtgc tccacagcga ctctctgaga agaggaactg gactccccaa

121 gctatgctct atctgaaggg tgcacagggc cgccgcttcc tctccgacca gagccgtagg 181 aaggagcttg cagaccggcc gcctccagaa agacgaaacc cagatcttga actgctgact

241 ctcccagagg ctgcagccct gtttctggct tccttggaaa aatcacaaaa agatgaagga

301 gggaattttg ataaaagcga actcttggaa gacagactct tcaactggtg a

SEQ ID NO: 60

Amino acid sequence of mouse MGC 10946 encoded by the DNA sequence shown in SEQ ID NO: 59.

MKGPSVLAVTAVVLLLVLSALENSSGAPQRLSEKRNWTPQAMLYLKGAQGRRFLSDQSRR KELADRPPPERRNPDLELLTLPEAAALFLASLEKSQKDEGGNFDKSELLEDRLFNW

SEQIDNO:61 genomic|Rattusnorvegicuscomputationaltranscriptpredictionfromgenomic

1 atgaaggggc cgagcatcct ggccgtggca gccttggccc ttctcctggt gctgtctgtt

61 ctggaaaact ccagcggtgc tccgcagaga ctctctgaga agaggaactg gactccccaa

121 gccatgctct atctgaaggg cgcacagggc caccgcttca tctcagacca gagtcgcagg

181 aaggagcttg cagaccggcc gcctccagaa agacgaaacc caaatcttca actgctgact 241 ctcccagagg ctgcagccct gtttctggct tccttggaaa aaccacaaaa agatgaagga

301 ggggattttg ataaaagcaa actcctggaa gacagacgct tttactggtg a

SEQIDNO: 62

Amino acid sequence of rat MGC 10946 encoded by the DNA sequence shown in SEQ ID NO: 61.

MKGPSILAVAALALLLVLSVLENSSGAPQRLSEKRNWTPQAMLYLKGAQGHRFISDQSRR KELADRPPPERRNPNLQLLTLPEAAALFLASLEKPQKDEGGDFDKSKLLEDRRFYW

SEQ ID NO: 63 gi|40254425|ref|NM_000906.2| Homo sapiens natriuretic peptide receptor A/guanylate cyclase A (atrionatriuretic peptide receptor A) (NPRl ), mRNA

1 ggttccctcc ggatagccgg agacttgggc cggccggacg ccccttctgg cacactccct

61 ggggcaggcg ctcacgcacg ctacaaacac acactcctct ttcctccctc gcgcgccctc

121 tctcatcctt cttcacgaag cgctcactcg caccctttct ctctctctct ctctctctaa 181 cacgcacgca cactcccagt tgttcacact cgggtcctct ccagcccgac gttctcctgg

241 cacccacctg ctccgcggcg ccctgcgcgc ccccctcggt cgcgcccctt gcgctctcgg

301 cccagaccgt cgcagctaca gggggcctcg agccccgggg tgagcgtccc cgtcccgctc

361 ctgctccttc ccatagggac gcgcctgatg cctgggaccg gccgctgagc ccaaggggac

421 cgaggaggcc atggtaggag cgctcgcctg ctgcggtgcc cgctgaggcc atgccggggc

481 cccggcgccc cgctggctcc cgcctgcgcc tgctcctgct cctgctgctg ccgccgctgc

541 tgctgctgct ccggggcagc cacgcgggca acctgacggt agccgtggta ctgccgctgg

601 ccaatacctc gtacccctgg tcgtgggcgc gcgtgggacc cgccgtggag ctggccctgg

661 cccaggtgaa ggcgcgcccc gacttgctgc cgggctggac ggtccgcacg gtgctgggca

721 gcagcgaaaa cgcgctgggc gtctgctccg acaccgcagc gcccctggcc gcggtggacc

781 tcaagtggga gcacaacccc gctgtgttcc tgggccccgg ctgcgtgtac gccgccgccc

841 cagtggggcg cttcaccgcg cactggcggg tcccgctgct gaccgccggc gccccggcgc

901 tgggcttcgg tgtcaaggac gagtatgcgc tgaccacccg cgcggggccc agctacgcca

961 agctggggga cttcgtggcg gcgctgcacc gacggctggg ctgggagcgc caagcgctca

1021 tgctctacgc ctaccggccg ggtgacgaag agcactgctt cttcctcgtg gaggggctgt

1081 tcatgcgggt ccgcgaccgc ctcaatatta cggtggacca cctggagttc gccgaggacg

1141 acctcagcca ctacaccagg ctgctgcgga ccatgccgcg caaaggccga gttatctaca

1201 tctgcagctc ccctgatgcc ttcagaaccc tcatgctcct ggccctggaa gctggcttgt

1261 gtggggagga ctacgttttc ttccacctgg atatctttgg gcaaagcctg caaggtggac

1321 agggccctgc tccccgcagg ccctgggaga gaggggatgg gcaggatgtc agtgcccgcc

1381 aggcctttca ggctgccaaa atcattacat ataaagaccc agataatccc gagtacttgg

1441 aattcctgaa gcagttaaaa cacctggcct atgagcagtt caacttcacc atggaggatg

1501 tcctggtgaa caccatccca gcatccttcc acgacgggct cctgctctat atccaggcag

1561 tgacggagac tctggcacat gggggaactg ttactgatgg ggagaacatc actcagcgga

1621 tgtggaaccg aagctttcaa ggtgtgacag gatacctgaa aattgatagc agtggcgatc

1681 gggaaacaga cttctccctc tgggatatgg atcccgagaa tggtgccttc agggttgtac

1741 tgaactacaa tgggacttcc caagagctgg tggctgtgtc ggggcgcaaa ctgaactggc

1801 ccctggggta ccctcctcct gacatcccca aatgtggctt tgacaacgaa gacccagcat

1861 gcaaccaaga tcacctttcc accctggagg tgctggcttt ggtgggcagc ctctccttgc

1921 tcggcattct gattgtctcc ttcttcatat acaggaagat gcagctggag aaggaactgg

1981 cctcggagct gtggcgggtg cgctgggagg acgttgagcc cagtagcctt gagaggcacc

2041 tgcggagtgc aggcagccgg ctgaccctga gcgggagagg ctccaattac ggctccctgc

2101 taaccacaga gggccagttc caagtctttg ccaagacagc atattataag ggcaacctcg

2161 tggctgtgaa acgtgtgaac cgtaaacgca ttgagctgac acgaaaagtc ctgtttgaac

2221 tgaagcatat gcgggatgtg cagaatgaac acctgaccag gtttgtggga gcctgcaccg

2281 acccccccaa tatctgcatc ctcacagagt actgtccccg tgggagcctg caggacattc

2341 tggagaatga gagcatcacc ctggactgga tgttccggta ctcactcacc aatgacatcg

2401 tcaagggcat gctgtttcta cacaatgggg ctatctgttc ccatgggaac ctcaagtcat

2461 ccaactgcgt ggtagatggg cgctttgtgc tcaagatcac cgactatggg ctggagagct

2521 tcagggacct ggacccagag caaggacaca ccgtttatgc caaaaagctg tggacggccc

2581 ctgagctcct gcgaatggct tcaccccctg tgcggggctc ccaggctggt gacgtataca

2641 gctttgggat catccttcag gagattgccc tgaggagtgg ggtcttccac gtggaaggtt

2701 tggacctgag ccccaaagag atcatcgagc gggtgactcg gggtgagcag ccccccttcc

2761 ggccctccct ggccctgcag agtcacctgg aggagttggg gctgctcatg cagcggtgct

2821 gggctgagga cccacaggag aggccaccat tccagcagat ccgcctgacg ttgcgcaaat

2881 ttaacaggga gaacagcagc aacatcctgg acaacctgct gtcccgcatg gagcagtacg

2941 cgaacaatct ggaggaactg gtggaggagc ggacccaggc atacctggag gagaagcgca

3001 aggctgaggc cctgctctac cagatcctgc ctcactcagt ggctgagcag ctgaagcgtg

3061 gggagacggt gcaggccgaa gcctttgaca gtgttaccat ctacttcagt gacattgtgg

3121 gtttcacagc gctgtcggcg gagagcacgc ccatgcaggt ggtgaccctg ctcaatgacc

3181 tgtacacttg ctttgatgct gtcatagaca actttgatgt gtacaaggtg gagacaattg

3241 gcgatgccta catggtggtg tcagggctcc ctgtgcggaa cgggcggcta cacgcctgcg

3301 aggtagcccg catggccctg gcactgctgg atgctgtgcg ctccttccga atccgccacc

3361 ggccccagga gcagctgcgc ttgcgcattg gcatccacac aggacctgtg tgtgctggag

3421 tggtgggact gaagatgccc cgttactgtc tctttgggga tacagtcaac acagcctcaa

3481 gaatggagtc taatggggaa gccctgaaga tccacttgtc ttctgagacc aaggctgtcc

3541 tggaggagtt tggtggtttc gagctggagc ttcgagggga tgtagaaatg aagggcaaag

3601 gcaaggttcg gacctactgg ctccttgggg agagggggag tagcacccga ggctgacctg

3661 cctcctctcc tatccctcca cacctcccct accctgtgcc agaagcaaca gaggtgccag

3721 gcctcagcct cacccacagc agccccatcg ccaaaggatg gaagtaattt gaatagctca

3781 ggtgtgctta ccccagtgaa gacaccagat aggacctctg agaggggact ggcatggggg 3841 gatctcagag cttacaggct gagccaagcc cacggccatg cacagggaca ctcacacagg 3901 cacacgcacc tgctctccac ctggactcag gccgggctgg gctgtggatt cctgatcccc 3961 tcccctcccc atgctctcct ccctcagcct tgctaccctg tgacttactg ggaggagaaa 4021 gagtcacctg aaggggaaca tgaaaagaga ctaggtgaag agagggcagg ggagcccaca 4081 tctggggctg gcccacaata cctgctcccc cgaccccctc cacccagcag tagacacagt 4141 gcacagggga gaagaggggt ggcgcagaag ggttgggggc ctgtatgcct tgcttctacc 4201 atgagcagag acaattaaaa tctttattcc aaaaaaaaaa aaaaaa

SEQ ID NO: 64

Amino acid sequence of human NPRl encoded by the DNA sequence shown in SEQ ID NO: 63.

MPGPRRPAGSRLRLLLLLLLPPLLLLLRGSHAGNLTVAWLPLANTSYPWSWARVGPAVE LALAQVKARPDLLPGWTVRTVLGSSENALGVCSDTAAPLAAVDLKWEHNPAVFLGPGCVY AAAPVGRFTAHWRVPLLTAGAPALGFGVKDEYALTTRAGPSYAKLGDFVAALHRRLGWER

QALMLYAYRPGDEEHCFFLVEGLFMRVRDRLNITVDHLEFAEDDLSHYTRLLRTMPRKGR VIYICSSPDAFRTLMLLALEAGLCGEDYVFFHLDIFGQSLQGGQGPAPRRPWERGDGQDV SARQAFQAAKIITYKDPDNPEYLEFLKQLKHLAYEQFNFTMEDVLVNTIPASFHDGLLLY IQAVTETLAHGGTVTDGENITQRMWNRSFQGVTGYLKIDSSGDRETDFSLWDMDPENGAF RVVLNYNGTSQELVAVSGRKLNWPLGYPPPDIPKCGFDNEDPACNQDHLSTLEVLALVGS LSLLGILIVSFFIYRKMQLEKELASELWRVRWEDVEPSSLERHLRSAGSRLTLSGRGSNY GSLLTTEGQFQVFAKTAYYKGNLVAVKRVNRKRIELTRKVLFELKHMRDVQNEHLTRFVG ACTDPPNICILTEYCPRGSLQDILENESITLDWMFRYSLTNDIVKGMLFLHNGAICSHGN LKSSNCWDGRFVLKITDYGLESFRDLDPEQGHTVYAKKLWTAPELLRMASPPVRGSQAG DVYSFGIILQEIALRSGVFHVEGLDLSPKEIIERVTRGEQPPFRPSLALQSHLEELGLLM QRCWAEDPQERPPFQQIRLTLRKFNRENSSNILDNLLSRMEQYANNLEELVEERTQAYLE EKRKAEALLYQILPHSVAEQLKRGETVQAEAFDSVTIYFSDIVGFTALSAESTPMQVVTL LNDLYTCFDAVIDNFDVYKVETIGDAYMVVSGLPVRNGRLHACEVARMALALLDAVRSFR IRHRPQEQLRLRIGIHTGPVCAGVVGLKMPRYCLFGDTVNTASRMESNGEALKIHLSSET KAVLEEFGGFELELRGDVEMKGKGKVRTYWLLGERGSSTRG

SEQIDNO: 65 gi|34328513|reflNM_008727.4|Musmusculusnatriureticpeptidereceptor1 (Nprl),mRNA

1 cagaaaccct cccaaactcc tatagccaca cacacctttc ccggccaaga tccaaacaaa

61 cctctacttt cctcttccct aggagccaga ctcccttcgg gtgctgcgct cgctctcacc

121 tgctctaaag cacctccgct ctcggacgct cccaattccg ccctcctgct cgacggcggg

181 acagtcgcag cctcggcagg cagcttgctc tcgccgctgc ggcttcaacc cagccccctc 241 cctcgctacg gctgggcgct cttgactccc gaccctcgcc tctgagcccg aggacggcga

301 tcagaccatg gtgacagcgc tgctccgtcg ctgcgctcgc tgaggccatg ccgcgttccc

361 gacgcgtccg tccgcgccta agggcgctgc tgctgctacc gccgctgctg ctgctccgaa

421 gcggccacgc gagcgacctg accgtggctg tggtgctgcc cgtgaccaac acctcgtacc

481 cgtggtcctg ggcgcgtgta gggccggcgg tggaactggc tctcgggagg gtgaaggctc 541 ggccggactt gctgccgggt tggacggtcc gtatggtgct gggcagcagc gagaacgcgg

601 cgggcgtctg ctccgacacc gctgcaccgc tggccgcggt ggatctcaag tgggagcaca

661 gccccgccgt gttcctgggc cccggctgcg tatactctgc tgccccggtg gaccgcttca

721 ccgcgcactg gcggttgccg ctgctgacgg ctggcgcccc ggctctgggc atcggggtga

781 aggatgagta cgcgttaacc acccgcacag gacccagcca tgtcaagctg ggcgacttcg 841 tgacggcgct gcatcgacgg ctgggctggg agcaccaggc gcttgtgctc tatgcagatc

901 ggctgggcga cgaccggccg tgcttcttca tagtggaggg gctgtacatg cgggtgcgtg

961 agcgactcaa catcacagta aatcaccagg agttcgtcga gggcgacccg gaccactaca

1021 ccaagctact gcggaccgtg cagcgcaagg gcagagttat ctacatctgc agttctccgg

1081 atgccttcag gaatctgatg cttttggccc tggatgctgg cctgactggg gaggactatg 1141 ttttcttcca cctggatgtg tttgggcaaa gccttcaggg tgctcagggc cctgttccag

1201 agaagccctg ggaaagagac gatgggcagg ataggagagc ccgccagcgc tttcaggctg

1261 caaaaattat tacttacaaa gaacccgata atcctgagta cttggaattc ctgaagcagc

1321 taaaactctt ggctgacaag aaattcaact tcaccatgga ggatggcctg aaaaatatca 1381 tcccagcatc cttccatgac gggctcctgc tctatgtcca ggcagtgaca gagactctgg 1441 cacagggggg cactgtcact gatggagaga acatcactca gcggatgtgg aaccgaagct 1501 tccaaggtgt gacaggatac ctgaaaattg atagaaatgg agatcgggac actgattctc 1561 ctctctggga tatggacccc gagacaggtg ccttcagggt tgtcctgaac tttaatggta 1621 cttcccagga gctgatggct gtgtcagaac acagattata ctggcctctg ggatacccac 1681 ctcctgacat ccctaaatgt ggctttgaca atgaggaccc agcctgcaac caagaccact 1741 tttccacact ggaggttctg gctttggtgg gcagcctctc tctggttagc tttctgatcg 1801 tgtctttctt catatacagg aagatgcagc tggaaaagga gctggtctca gagttgtggc 1861 gggtgcgctg ggaggacttg cagcccagca gcctggagag gcaccttcgg agcgctggca 1921 gtcggctgac cctgagtggg cgaggctcca attatggctc cctgctaacc acggagggcc 1981 agttccaagt ctttgccaag acagcatact ataagggcaa cctcgtggct gtgaaacgtg 2041 tgaaccggaa acgcattgag ttgacacgaa aagtcctgtt tgaacttaaa catatgcggg 2101 atgtgcagaa tgagcaattg accagatttg tgggagcttg taccgaccct cccaacatct 2161 gtatcctcac agagtactgt ccccgtggaa gcctacagga cattctagag aatgagagta 2221 ttaccctgga ctggatgttt cggtactcac tcaccaatga cattgtcaag ggaatgctct 2281 ttctacacaa cggggccatt tgttcccatg ggaacctcaa gtcatccaac tgcgtggtag 2341 atggacgttt tgtgttaaag atcacagact atgggctcga gagcttcaga gacccggagc 2401 cagagcaagg acacaccctc tttgccaaaa aactgtggac tgcacctgag ctcctgcgaa 2461 tggcttcccc acctgcccgt ggctcccaag ctggggatgt ctacagtttt ggtatcatcc 2521 ttcaggaaat tgccctaaga agtggggtct tctatgtgga aggtttggac ctcagcccaa 2581 aagagatcat tgagcgtgtg actcggggtg agcagccccc attccgacct tccatggatc 2641 tgcagagcca cctggaggaa ctggggcagc tgatgcagag gtgctgggca gaggatcctc 2701 aggagcggcc accctttcaa cagatccgcc tggcgctgcg caagttcaac aaggagaaca 2761 gcagcaacat cctggacaac ctgctgtcac gcatggaaca gtacgccaac aacctggagg 2821 aactggtaga ggagagaaca cagccttatc tggaggagaa gcgcaaagct gaggccctgc 2881 tttaccagat tctgcctcac tctgtggctg agcagctgaa gagaggcgag acagtccagg 2941 ctgaggcatt tgatagtgtt actatctatt tcagtgatat cgtgggcttt acagctcttt 3001 cagcagagag cacacccatg caggtggtca ccctgctcaa tgatctgtac acctgttttg 3061 atgctgtcat agacaacttt gatgtgtaca aggtagagac cattggtgat gcttacatgg 3121 tggtatcagg gctcccagtg aggaatggac agctccatgc ccgagaggta gcccgaatgg 3181 cacttgcact gctcgatgct gtacgctcct tccgcatcgg ccataggccc caggaacagc 3241 tgcgcttgcg cattggaatt cacacaggtc ctgtgtgtgc tggtgtggta gggctaaaga 3301 tgccccgata ctgcctcttt ggagacacag tcaacacagc ttcaagaatg gagtctaatg 3361 gggaagccct caggatccac ttgtcttcgg agaccaaggc tgtgctggaa gagttcgatg 3421 gtttcgagct ggagctccga ggggatgtgg aaatgaaggg caaaggcaag gttcgttcct 3481 attggctcct cggggaccgg ggatgcagct ctcgagcctg acctactgcc ctgctattcc 3541 ttgtcacctc ccctccctat cccagcaatg acacgggtct ccaacttccc cctctcccac 3601 agcagctcag ccactgtgga aagattaggg acctaaccag cgcagtcatc agatgtgacc 3661 tctgagagag gatggagatg gtggggactg gagggggact cctaagttta tagggctgac 3721 tgaaataccc agtcactccc gtagcacatg ccccgccccc cccccgcccc cccactcagc 3781 tgcctagcag acagtgattc cttctgccgc cctcaactta gctccactgt gagttagagg 3841 gagggaaatt gccacctgaa ggaaagagaa aagagattct cggggtttgc aggaggcagg 3901 cagtcctgtg tcacaaatac tcccctcact cccagtccac cacctgcccc accgacttcc 3961 cttcccacac agtgcactga ggagaagaga ggcatggggt tgccttgctt ctcctatgag 4021 caaaacccat taaagtcttt attcctgtg

SEQEDNO: 66

Amino acid sequence of mouse NPRl encoded by the DNA sequence shown in SEQ ED NO: 65.

MPRSRRVRPRLRALLLLPPLLLLRSGHASDLTVAVVLPVTNTSYPWSWARVGPAVELALG RVKARPDLLPGWTVRMVLGSSENAAGVCSDTAAPLAAVDLKWEHSPAVFLGPGCVYSAAP

VDRFTAHWRLPLLTAGAPALGIGVKDEYALTTRTGPSHVKLGDFVTALHRRLGWEHQALV

LYADRLGDDRPCFFIVEGLYMRVRERLNITVNHQEFVEGDPDHYTKLLRTVQRKGRVIYI

CSSPDAFRNLMLLALDAGLTGEDYVFFHLDVFGQSLQGAQGPVPEKPWERDDGQDRRARQ

RFQAAKIITYKEPDNPEYLEFLKQLKLLADKKFNFTMEDGLKNIIPASFHDGLLLYVQAV TETLAQGGTVTDGENITQRMWNRSFQGVTGYLKIDRNGDRDTDSPLWDMDPETGAFRVVL

NFNGTSQELMAVSEHRLYWPLGYPPPDIPKCGFDNEDPACNQDHFSTLEVLALVGSLSLV

SFLIVSFFIYRKMQLEKELVSELWRVRWEDLQPSSLERHLRSAGSRLTLSGRGSNYGSLL TTEGQFQVFAKTAYYKGNLVAVKRVNRKRIELTRKVLFELKHMRDVQNEQLTRFVGACTD PPNICILTEYCPRGSLQDILENESITLDWMFRYSLTNDIVKGMLFLHNGAICSHGNLKSS NCWDGRFVLKITDYGLESFRDPEPEQGHTLFAKKLWTAPELLRMASPPARGSQAGDVYS FGIILQEIALRSGVFYVEGLDLSPKEIIERVTRGEQPPFRPSMDLQSHLEELGQLMQRCW AEDPQERPPFQQIRLALRKFNKENSSNILDNLLSRMEQYANNLEELVEERTQPYLEEKRK AEALLYQILPHSVAEQLKRGETVQAEAFDSVTIYFSDIVGFTALSAESTPMQWTLLNDL YTCFDAVIDNFDVYKVETIGDAYMWSGLPVRNGQLHAREVARMΆLALLDAVRSFRIGHR PQEQLRLRIGIHTGPVCAGWGLKMPRYCLFGDTVNTASRMESNGEALRIHLSSETKAVL EEFDGFELELRGDVEMKGKGKVRSYWLLGDRGCSSRA SEQIDNO:67 gi|6981279|ref[NM_012613.1| Rattus norvegicus natriuretic peptide receptor 1 (Nprl), mRNA i actcctgggg caagcgcgag cgcacactcc cctttccttg ctggcgctcc ctctcccctc

61 gctctctctc tctagaccgt cctctccttc cctcgctctc caccgactcc cttcgggtgc

121 tgtgcttgct cccacctgct ctgaagcgct ctccgctctc ggacgctccc aatttagcgc

181 tcctgctcga cggccgaacc gtcgcagcct ccgcaggcag cgtgccctcg gggttgcggc

241 ttcaacccac cccagcttcc tccctcgcta cgactcgggc gccctggacg ttcgaccctc

301 gccgctgagc ccgaggatgg cgagcagacc atggtgacag cgctgcccgg tcgctgcact

361 cgctgaggcc atgccgggct cccgacgcgt ccgtccgcgc ctaagggcgc tgctgctgct

421 gccgccgctt ctgctactcc ggggcggcca cgcgagcgac ctgaccgtgg ctgtggtgct

481 gccgctgacc aacacctcgt acccgtggtc ctgggcgcgt gtagggccgg ccgtggaact

541 ggctctcgcg cgggtgaagg ctcggccgga cttgctgccg ggttggacgg tccgcatggt

601 gctgggcagc agtgagaacg cggcgggcgt ctgctcggac accgccgcac cgctggccgc

661 ggtggacctc aagtgggagc acagccccgc ggtgttcctg ggccccggct gcgtctactc

721 cgctgccccg gtggggcgct tcaccgcgca ctggcgggtg ccgctgctga ccgccggcgc

781 cccggctctg ggcatcgggg tcaaggatga gtatgcgcta accacccgca caggacccag

841 ccatgtcaag ctgggcgatt tcgtgacggc gctgcatcga cggctgggct gggagcacca

901 ggcgctggtg ctctatgcag atcggctggg cgacgaccgg ccttgcttct tcatagtgga

961 ggggctgtac atgcgggtgc gtgaacgcct caacatcaca gtgaatcacc aggagttcgt

1021 cgagggcgac ccggaccact accccaagct actgcgggcc gtgcggcgaa agggcagagt

1081 tatctacatc tgcagttctc cggatgcctt caggaatctg atgcttctgg ccctgaacgc

1141 tggcctgact ggggaggact atgttttctt ccacctggat gtgtttgggc aaagccttaa

1201 gagtgctcag ggccttgttc cccagaaacc ctgggaaaga ggagatgggc aggacaggag

1261 tgcccgccag gcctttcagg ctgccaaaat tattacttac aaagagcctg ataatcctga

1321 gtacttggaa ttcctgaagc agctgaaact cttggctgac aagaagttca acttcaccgt

1381 ggaggatggc ctgaagaata tcatcccagc ctccttccac gacgggctcc tgctctatgt

1441 ccaggcagtg acagagactc tggcacaggg gggaactgtc acagatggag agaacatcac

1501 tcagcggatg tggaaccgaa gcttccaagg tgtgacagga tacctgaaaa ttgatagaaa

1561 cggagatcgg gacaccgatt tctctctctg ggatatggat ccagagacgg gtgccttcag

1621 ggttgtcctg aactataatg gtacttccca ggagctaatg gctgtgtcag aacacaaatt

1681 atactggcct ctgggatatc cacctcctga cgtccctaaa tgtggctttg acaatgagga

1741 cccagcctgc aaccaagacc acttttccac actggaggtt ctggctttgg tgggcagcct

1801 ctctctgatt agctttctga ttgtgtcttt cttcatatac aggaagatgc agctggaaaa

1861 ggagctggtc tcagagttgt ggcgggtgcg ctgggaggac ttgcagccca gcagcctgga

1921 gaggcatctt cggagcgctg gcagccggct gaccctgagt gggcgaggct ccaattatgg

1981 ctccctgcta accaccgagg gccagttcca agtctttgcc aagacagcat actataaggg

2041 caaccttgtg gctgtgaaac gtgtgaaccg gaaacgcatt gagttgacac gaaaagtcct

2101 gtttgaactt aaacatatgc gggatgtgca gaatgagcac ttgacaagat ttgtgggtgc

2161 ttgtaccgac ccccccaaca tctgtatcct cacagagtac tgtccccgtg gaagcctaca

2221 ggacattcta gagaatgaga gtatcaccct ggactggatg tttcggtact cgctcaccaa

2281 tgacattgtc aagggaatgc tctttctaca caatggggcc atttgttccc atgggaacct

2341 caagtcatcc aactgtgtgg tagacgggcg cttcgtgtta aagatcacag actacggtct

2401 tgagagcttc agagacccgg agccagagca aggacacacc ctctttgcca aaaaattgtg

2461 gacggcacct gagctcctgc gaatggcttc gccacctgcc cgtggctccc aagctgggga

2521 tgtgtacagc tttggtatca tcctgcagga gattgcccta agaagtgggg tcttctatgt

2581 ggaaggtttg gacctcagcc caaaagagat cattgagcgt gtgactcggg gtgagcagcc

2641 cccattccga ccctccatgg atctgcagag ccacctggag gaactggggc agctgatgca 2701 gcggtgctgg gcagaggacc cacaggagcg gccacccttt cagcagattc gcctggcgct

2761 gcgcaagttc aacaaggaga acagcagcaa catcctggac aacctgctgt cacgcatgga 2821 gcagtatgct aacaacctgg aggaactggt agaggagaga acacaagctt atctggagga

2881 gaagcgcaaa gctgaggcct tgctttacca gattctgcct cactccgtgg ctgagcagct 2941 gaagagaggc gagacagtcc aggctgaggc ctttgatagt gttaccatct acttcagtga

3001 tattgtgggc tttacagctc tttcagcaga aagcacaccc atgcaggtgg tgactctgct 3061 caatgatctg tacacctgtt ttgatgctgt catagacaac tttgatgtgt acaaggtgga 3121 gaccattggt gatgcttaca tggtggtgtc agggctccca gtgcggaatg gacaactcca 3181 cgcccgagag gtggcccgaa tggcacttgc actactggat gctgtgcgct ccttccgcat 3241 ccgccatagg ccccaggaac agctgcgctt gcgcattggc atccacacag gtcctgtgtg 3301 tgctggtgtg gtagggctaa agatgccccg atactgcctc tttggagaca cagtcaacac 3361 agcttcaaga atggagtcta atggagaagc cctcaagatc cacttgtctt cagagaccaa 3421 ggctgtgctg gaagagttcg atggtttcga gctggagctc cgaggggatg tggaaatgaa 3481 gggcaaaggc aaggttcgga cctattggct cctgggggag cggggatgta gcactcgagg 3541 ctgacctact gccctgctgt tccttgtcac ccctcctccc tgtgccagag gtgacagagg 3601 tgtccagctt ccacctctcc cacagcagcc cagccactgt ggaaggatta gggacctgac 3661 cagcacagtc accagatgtg acctctgaga gaggatggag atggtgggga ctgcagggga 3721 cacctaagtt tgtaggactg actgaaacac acagtccctc ccatggcacc cttgtggcac 3781 acatgcccag tcccaccctt actctgctgc ctagattggg acagcgattc cttctctgcc 3841 ctcaacttag ctccactgtg acttataggg agggaattgc cacctgaagg aaacagaaag 3901 aggttagagt ttgcaggagg cgggcagtcc tgtgtcacaa atactcccct cacttccagc 3961 ccaccacctg ccccacagac tttggacaca gctcactgag gagaagagaa gctgccggtt 4021 accttgcttc tcctgtgaac caaaccatta aagtctttat tcctgtga

SEQIDNO:68 AminoacidsequenceofratNPRl encodedbytheDNAsequenceshowninSEQIDNO:67.

MPGSRRVRPRLRALLLLPPLLLLRGGHASDLTVAWLPLTNTSYPWSWARVGPAVELALA RVKARPDLLPGWTVRMVLGSSENAAGVCSDTAAPLAAVDLKWEHSPAVFLGPGCVYSAAP VGRFTAHWRVPLLTAGAPALGIGVKDEYALTTRTGPSHVKLGDFVTALHRRLGWEHQALV LYADRLGDDRPCFFIVEGLYMRVRERLNITVNHQEFVEGDPDHYPKLLRAVRRKGRVIYI CSSPDAFRNLMLLALNAGLTGEDYVFFHLDVFGQSLKSAQGLVPQKPWERGDGQDRSARQ AFQAAKIITYKEPDNPEYLEFLKQLKLLADKKFNFTVEDGLKNIIPASFHDGLLLYVQAV TETLAQGGTVTDGENITQRMWNRSFQGVTGYLKIDRNGDRDTDFSLWDMDPETGAFRVVL NYNGTSQELMAVSEHKLYWPLGYPPPDVPKCGFDNEDPACNQDHFSTLEVLALVGSLSLI SFLIVSFFIYRKMQLEKELVSELWRVRWEDLQPSSLERHLRSAGSRLTLSGRGSNYGSLL TTEGQFQVFAKTAYYKGNLVAVKRVNRKRIELTRKVLFELKHMRDVQNEHLTRFVGACTD PPNICILTEYCPRGSLQDILENESITLDWMFRYSLTNDIVKGMLFLHNGAICSHGNLKSS NCVVDGRFVLKITDYGLESFRDPEPEQGHTLFAKKLWTAPELLRMASPPARGSQAGDVYS FGIILQEIALRSGVFYVEGLDLSPKEIIERVTRGEQPPFRPSMDLQSHLEELGQLMQRCW AEDPQERPPFQQIRLALRKFNKENSSNTLDNLLSRMEQYANNLEELVEERTQAYLEEKRK AEALLYQILPHSVAEQLKRGETVQAEAFDSVTIYFSDIVGFTALSAESTPMQVVTLLNDL YTCFDAVIDNFDVYKVETIGDAYMVVSGLPVRNGQLHAREVARMALALLDAVRSFRIRHR PQEQLRLRIGIHTGPVCAGVVGLKMPRYCLFGDTVNTASRMESNGEALKIHLSSETKAVL EEFDGFELELRGDVEMKGKGKVRTYWLLGERGCSTRG

SEQIDNO:69 gi|7110640|ref|NM_012268.11HomosapiensphospholipaseD3(PLD3),mRNA

1 ctctttataa tttagtttcc atagaagtta tatgtgcatt taaaaaaatt caatgctgga

61 gcgaccgtgt ctggggagcc gagccccgct tctcgctgcg gtgagcccgg actggggcac

121 gcactgcgca gactccccgc tgcagtgggc ggagtcccac aggccccgcc cctcctccca

181 ccctcgttca gcctgtccag acagaagctg gggcccagcg gaggtagcag cagacgcctg 241 agagcgaggc cgaggccctc agggtttgga gaccctgaca cacccacctt ctcacctggg

301 ctctgcgtat cccccagcct tgagggaaga tgaagcctaa actgatgtac caggagctga

361 aggtgcctgc agaggagccc gccaatgagc tgcccatgaa tgagattgag gcgtggaagg

421 ctgcggaaaa gaaagcccgc tgggtcctgc tggtcctcat tctggcggtt gtgggcttcg 481 gagcctgatg actcagctgt ttctatggga atacggcgac ttgcatctct ttgggcccaa

541 ccagcgccca gccccctgct atgacccttg cgaagcagtg ctggtggaaa gcattcctga

601 gggcctggac ttccccaatg cctccacggg gaacccttcc accagccagg cctggctggg

661 cctgctcgcc ggtgcgcaca gcagcctgga catcgcctcc ttctactgga ccctcaccaa

721 caatgacacc cacacgcagg agccctctgc ccagcagggt gaggaggtcc tccggcagct

781 gcagaccctg gcaccaaagg gcgtgaacgt ccgcatcgct gtgagcaagc ccagcgggcc

841 ccagccacag gcggacctgc aggctctgct gcagagcggt gcccaggtcc gcatggtgga

901 catgcagaag ctgacccatg gcgtcctgca taccaagttc tgggtggtgg accagaccca

961 cttctacctg ggcagtgcca acatggactg gcgttcactg acccaggtca aggagctggg

1021 cgtggtcatg tacaactgca gctgcctggc tcgagacctg accaagatct ttgaggccta

1081 ctggttcctg ggccaggcag gcagctccat cccatcaact tggccccggt tctatgacac

1141 ccgctacaac caagagacac caatggagat ctgcctcaat ggaacccctg ctctggccta

1201 cctggcgagt gcgcccccac ccctgtgtcc aagtggccgc actccagacc tgaaggctct

1261 actcaacgtg gtggacaatg cccggagttt catctacgtc gctgtcatga actacctgcc

1321 cactctggag ttctcccacc ctcacaggtt ctggcctgcc attgacgatg ggctgcggcg

1381 ggccacctac gagcgtggcg tcaaggtgcg cctgctcatc agctgctggg gacactcgga

1441 gccatccatg cgggccttcc tgctctctct ggctgccctg cgtgacaacc atacccactc

1501 tgacatccag gtgaaactct ttgtggtccc cgcggatgag gcccaggctc gaatcccata

1561 tgcccgtgtc aaccacaaca agtacatggt gactgaacgc gccacctaca tcggaacctc

1621 caactggtct ggcaactact tcacggagac ggcgggcacc tcgctgctgg tgacgcagaa

1681 tgggaggggc ggcctgcgga gccagctgga ggccattttc ctgagggact gggactcccc

1741 ttacattcat gaccttgaca cctcagctga cagcgtgggc aacgcctgcc gcctgctctg

1801 aggcccgatc cagtgggcag gccaaggcct gctgggcccc cgcggaccca ggtgctctgg

1861 gtcacggtcc ctgtccccgc acccccgctt ctgtctgccc cattgtggct cctcaggctc

1921 tctcccctgc tctcccacct ctacctccac ccccaccggc ctgacgctgt ggccccggga

1981 cccagcagag ctgggggagg gatcagcccc caaagaaatg ggggtgcatg ctggcctgcc

2041 ccctggccca cccccacttt ccagggcaaa aagggcccag ggttataata agtaaataac

2101 ttgtctgtaa aaaaaaaaaa aaaaaaaaaa a

SEQIDNO:70 AminoacidsequenceofhumanPLD3 encodedbytheDNAsequenceshowninSEQIDNO: 69.

MTQLFLWEYGDLHLFGPNQRPAPCYDPCEAVLVESIPEGLDFPNASTGNPSTSQAWLGLL AGAHSSLDIASFYWTLTNNDTHTQEPSAQQGEEVLRQLQTLAPKGVNVRIAVSKPSGPQP QADLQALLQSGAQVRMVDMQKLTHGVLHTKFWVVDQTHFYLGSANMDWRSLTQVKELGVV MYNCSCLARDLTKIFEAYWFLGQAGSSIPSTWPRFYDTRYNQETPMEICLNGTPALAYLA SAPPPLCPSGRTPDLKALLNVVDNARSFIYVAVMNYLPTLEFSHPHRFWPAIDDGLRRAT YERGVKVRLLISCWGHSEPSMRAFLLSLAALRDNHTHSDIQVKLFVVPADEAQARIPYAR VNHNKYMVTERATYIGTSNWSGNYFTETAGTSLLVTQNGRGGLRSQLEAIFLRDWDSPYI HDLDTSADSVGNACRLL SEQIDNO:71

ENST00000335834 cDNA sequence, EnsEMBL transcript [Homo sapiens]

1 gtcaggcggg gatacagcct ggaaggtaat gcatgtccat ggtacacaaa ttcacaagtt

61 tggagaccct gacacaccca ccttctcacc tgggctctgc gtatccccca gccttgaggg

121 aagatgaagc ctaaactgat gtaccaggag ctgaaggtgc ctgcagagga gcccgccaat 181 gagctgccca tgaatgagat tgaggcgtgg aaggctgcgg aaaagaaagc ccgctgggtc 241 ctgctggtcc tcattctggc ggttgtgggc ttcggagccc tgatgactca gctgtttcta 301 tgggaatacg gcgacttgca tctctttggg cccaaccagc gcccagcccc ctgctatgac 361 ccttgcgaag cagtgctggt ggaaagcatt cctgagggcc tggacttccc caatgcctcc 421 acggggaacc cttccaccag ccaggcctgg ctgggcctgc tcgccggtgc gcacagcagc 481 ctggacatcg cctccttcta ctggaccctc accaacaatg acacccacac gcaggagccc 541 tctgcccagc agggtgagga ggtcctccgg cagctgcaga ccctggcacc aaagggcgtg 601 aacgtccgca tcgctgtgag caagcccagc gggccccagc cacaggcgga cctgcaggct 661 ctgctgcaga gcggtgccca ggtccgcatg gtggacatgc agaagctgac ccatggcgtc 721 ctgcatacca agttctgggt ggtggaccag acccacttct acctgggcag tgccaacatg

781 gactggcgtt cactgaccca ggtcaaggag ctgggcgtgg tcatgtacaa ctgcagctgc

841 ctggctcgag acctgaccaa gatctttgag gcctactggt tcctgggcca ggcaggcagc

901 tccatcccat caacttggcc ccggttctat gacacccgct acaaccaaga gacaccaatg

961 gagatctgcc tcaatggaac ccctgctctg gcctacctgg cgagtgcgcc cccacccctg

1021 tgtccaagtg gccgcactcc agacctgaag gctctactca acgtggtgga caatgcccgg

1081 agtttcatct acgtcgctgt catgaactac ctgcccactc tggagttctc ccaccctcac

1141 aggttctggc ctgccattga cgatgggctg cggcgggcca cctacgagcg tggcgtcaag

1201 gtgcgcctgc tcatcagctg ctggggacac tcggagccat ccatgcgggc cttcctgctc

1261 tctctggctg ccctgcgtga caaccatacc cactctgaca tccaggtgaa actctttgtg

1321 gtccccgcgg atgaggccca ggctcgaatc ccatatgccc gtgtcaacca caacaagtac

1381 atggtgactg aacgcgccac ctacatcgga acctccaact ggtctggcaa ctacttcacg

1441 gagacggcgg gcacctcgct gctggtgacg cagaatggga ggggcggcct gcggagccag

1501 ctggaggcca ttttcctgag ggactgggac tccccttaca gccatgacct tgacacctca

1561 gctgacagcg tgggcaacgc ctgccgcctg ctctgaggcc cgatccagtg ggcaggccaa

1621 ggcctgctgg gcccccgcgg acccaggtgc tctgggtcac ggtccctgtc cccgcgcccc

1681 cgcttctgtc tgccccattg tggctcctca ggctctctcc cctgctctcc cacctctacc

1741 tccaccccca ccggcctgac gctgtggccc cgggacccag cagagctggg ggagggatca

1801 gcccccaaag aaatgggggt gcatgctggg cctggccccc tggcccaccc ccactttcca

1861 gggcaaaaag ggcccagggt tataataagt aaataacttg tctgt

SEQIDNO:72

AminoacidsequenceofhumanPLD3variantORFnumber1 encodedbytheDNAsequence showninSEQIDNO: 71.

MKPKLMYQELKVPAEEPANELPMNEIEAWKAAEKKARWVLLVLILAVVGFGALMTQLFLW EYGDLHLFGPNQRPAPCYDPCEAVLVESIPEGLDFPNASTGNPSTSQAWLGLLAGAHSSL

DIASFYWTLTNNDTHTQEPSAQQGEEVLRQLQTLAPKGVNVRIAVSKPSGPQPQADLQAL

LQSGAQVRMVDMQKLTHGVLHTKFWVVDQTHFYLGSANMDWRSLTQVKELGVVMYNCSCL

ARDLTKIFEAYWFLGQAGSSIPSTWPRFYDTRYNQETPMEICLNGTPALAYLASAPPPLC

PSGRTPDLKALLNVVDNARSFIYVAVMNYLPTLEFSHPHRFWPAIDDGLRRATYERGVKV RLLISCWGHSEPSMRAFLLSLAALRDNHTHSDIQVKLFVVPADEAQARIPYARVNHNKYM

VTERATYIGTSNWSGNYFTETAGTSLLVTQNGRGGLRSQLEAIFLRDWDSPYSHDLDTSA

DSVGNACRLL

SEQIDNO: 73 gi|7242180|reflNM_011116.11 Mus musculus phospholipase D3 (Pld3), mRNA i tcagaaagga tcaagtctag cccccaccct gcccgcagtc tagcgcgact gcgcctgcgc

61 acaggtgggc gggaaggcgg ggctaggttc tggagtagaa gactctgacg tgcaggctgt 121 gatgtcacac ctgaacacag acaggcccac aggctgagga accggaagct gttctgtggg 181 caggaagaag gttgctcagg accacccctt tcccggttcg aggggagtca gccgacgcgc 241 gcgcactgcg cagactcctc gctgcagtgg gcgtgatccg tggaggtccc gcccctactc 301 agctgctcag acagaagctg gagccccacc gaagtagcag ccaacgtctg atttccagtc 361 cctgacacac ccacctagcc accttcgttc tgcagagtcc cccagcggcc aggcaatatg 421 aagcccaaac tgatgtacca ggagctgaag gtgcctgttg aggagcctgc gggagaactg 481 cccttgaatg aaatcgaggc atggaaggca gcagagaaga aagcccgctg ggtcctcctg 541 gtcctgatcc tggcggtagt gggcttcggt gccctgatga ctcagctgtt tctatgggaa 601 tacggggact tacatctatt tggaccaaat cagcgcccag ccccctgcta tgacccctgc 661 gaggcggtgc tggtggagag cattcctgag ggtctggagt ttcccaatgc caccacgagc 721 aacccctcca ctagccaggc ctggttgggc ctccttgccg gtgctcacag cagcctggac 781 atcgcatcct tctactggac cctcacaaat aatgacaccc acacgcaaga gccctctgcc 841 cagcagggtg aagaggttct tcagcagctt caggcactgg cacctcgagg tgtaaaggtt 901 cgcatcgctg tgagcaaacc caatgggcct ctggctgatc tgcagtctct gctacagagt 961 ggtgcccagg tccgcatggt ggacatgcag aagctgactc atggtgtcct gcacaccaag 1021 ttctgggtgg tggatcagac ccacttctac ctgggcagtg ccaacatgga ctggcggtcg 1081 ctgacccagg tcaaggagct gggcgtggtc atgtacaact gcagctgcct cgcccgggac 1141 ctcaccaaga tctttgaagc ctattggttc ctgggccagg caggtagctc catcccatca 1201 acctggccgc ggtcctttga cacccgatat aatcaagaaa caccaatgga gatctgcctc 1261 aatggcaccc cagctctggc ctacctagcg agtgcacccc caccactgtg tccaagtggc 1321 cgcaccccag acctgaaggc tctgctcaac gtggtggaca gtgcccgaag cttcatctac 1381 attgcggtta tgaactacct gcccaccatg gagttctctc atccacgcag gttctggcca 1441 gcgatcgatg atgggctgag acgggctgcg tatgaacgag gcgtcaaagt gcgcctgctc 1501 atcagctgct ggggacactc tgatccatcg atgcggtcct tcctgctctc cctggctgca 1561 cttcatgaca accatactca ctccgacatc caggtgaaac tgtttgtggt ccctacggat 1621 gagtcccagg cccgaatccc ctatgcccgt gtcaaccaca acaagtacat ggtgactgaa 1681 cgtgcctcat acattggaac ctccaactgg tctggaagct acttcacgga gacagcaggc 1741 acctccctgc tggtgacaca gaacgggcat ggtggcttgc gcagtcagct ggaggctgtt 1801 ttcctgagag actgggaatc cccatacagc cacgatctcg acacctcagc caacagtgtg 1861 ggcaatgcct gccgcctgct ttgaggctca gcccgacgga caggtcaaag ccttccaggc 1921 ctccttggac tcagctctgg gtcctggtta ctgtccccat gcccttgcct ctgtctatcc 1981 cgtgtggctc tgtactctcc actatactcc tgctgctacc tccaccgcca ctggcctgac 2041 actctggccc ctgtggacct agcagagctg gggattgggc cccaaagaag tgggggtgca 2101 tgctgggccc agacctttgg cccaccccca aagggccaag attataagta aataattgtc 2161 tgtaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2221 aaaaaaaaaa aaaaaaaaaa aaaaaa SEQIDNO:74

Amino acid sequence of mouse PLD3 encoded by the DNA sequence shown in SEQ ID NO: 73.

MKPKLMYQELKVPVEEPAGELPLNEIEAWKAAEKKARWVLLVLILAVVGFGALMTQLFLW EYGDLHLFGPNQRPAPCYDPCEAVLVESIPEGLEFPNATTSNPSTSQAWLGLLAGAHSSL DIASFYWTLTNNDTHTQEPSAQQGEEVLQQLQALAPRGVKVRIAVSKPNGPLADLQSLLQ SGAQVRMVDMQKLTHGVLHTKFWVVDQTHFYLGSANMDWRSLTQVKELGWMYNCSCLAR DLTKIFEAYWFLGQAGSSIPSTWPRSFDTRYNQETPMEICLNGTPALAYLASAPPPLCPS GRTPDLKALLNVVDSARSFIYIAVMNYLPTMEFSHPRRFWPAIDDGLRRAAYERGVKVRL LISCWGHSDPSMRSFLLSLAALHDNHTHSDIQVKLFWPTDESQARIPYARVNHNKYMVT ERASYIGTSNWSGSYFTETAGTSLLVTQNGHGGLRSQLEAVFLRDWESPYSHDLDTSANS VGNACRLL

SEQ ID NO: 75 gi|34855394|ref|XM_341811.1| Rattus norvegicus similar to schwannoma-associated protein (LOC361527), mRNA i tgatgtctca cctggataca gacaggacca caggctaagg aactgggagc tgttctgtgg

61 acaggaagaa ggttactcag gaccacccct tcccctgttg cggggagtca gccgacgacg 121 tgcacactgc gcagacgcct cgctgcagtg ggcgtgatcc gtggaggtcc cgccccttct 181 ttcctcccgc ccctactcag ctgctcaggc agaagctggg gccccaccga agtagcagcc 241 aacgtcggat ccctgacaca cccaccttgc cgcctccgtt ctgcagaggc ccccagctgc 301 caggcaatat gaagcctaaa ctgatgtacc aggagctgaa ggttcctgtt gaggaacctg 361 cgggagaact gcccatgaat gaaatcgagg catggaaggc agcagagaag aaagcccgtt 421 gggtcctcct tgtccttatc ctggcggtag tgggcttcgg tgccctgatg actcagctgt 481 ttctatggga atacggggac ttacatctat ttggcccgaa tcagcaccca gccccctgct 541 atgacccctg cgaggcggtg ctggtggaga gcattcccga ggggctggag tttcccaatg 601 ccaccacaag caacccctcc accagccagg cctggttggg cctccttgcc ggtgctcaca 661 gcagcctgga catcgcgtcc ttctactgga ctctcacaaa caatgatacc cacacgcaag 721 agccctctgc ccagcagggt gaagaggttc ttcagcagct tcaggctctg gcacctcgag 781 gtgtaaaggt tcgcatcgct gtgagcaaac ccaacggacc tctggctgat ctgcagtctc 841 tgctacagag tggtgcccag gtgcgcatgg tggacatgca gaagctgacc catggtgtcc 901 tgcacaccaa gttctgggtg gtggaccaga cccactttta cctgggcagt gccaacatgg 961 actggcgatc gctgacccag gtcaaggagc tgggcgtggt catgtacaac tgcagctgcc 1021 tggctcgcga cctcaccaag atttttgaag cctattggtt cctgggccag gcaggcagct 1081 ccatcccttc aacctggcca cggccctttg acacccggta caaccaagaa acaccgatgg 1141 agatctgcct caatggcacc ccagccctgg cctacctggc gagtgcaccc ccgccactgt 1201 gtccaggtgg ccgcacccca gacctgaagg cactgctcag cgtggtggac aacgcccgaa 1261 gcttcatcta cattgcagtt atgaactacc tgcccaccat ggagttctcc catccacgca 1321 ggttctggcc agcgattgat gatgggctaa gacgggctgc gtatgaacga ggcgtcaaag 1381 tgcgtttgct catcagctgc tggggacact ccgagccatc catgcggtcc ttcctgctct 1441 ccctggctgc ccttcgtgac aaccataccc actctgacat ccaggtgaaa ctgtttgtgg 1501 tccctgcgga tgaggcccaa gctcgaatcc cctatgcccg cgtcaaccac aacaagtaca 1561 tggtgactga acgcaccaca tacattggaa cctccaactg gtctggaagc tacttcacag 1621 agacggcagg cacctccctg ctggtgacac agaacgggca cggtggcttg cgcagccagc 1681 tggaggctgt tttcctgaga gactgggaat ccccatacag ccacaacctt gacacctcag 1741 ccgacagtgt gggcaatgcc tgccgcctgc tttga

SEQIDNO:76

AminoacidsequenceofratPLD3 encodedbytheDNAsequenceshowninSEQIDNO:75. MKPKLMYQELKVPVEEPAGELPMNEIEAWKAAEKKARWVLLVLILAVVGFGALMTQLFLW EYGDLHLFGPNQHPAPCYDPCEAVLVESIPEGLEFPNATTSNPSTSQΆWLGLLAGAHSSL DIASFYWTLTNNDTHTQEPSAQQGEEVLQQLQALAPRGVKVRIAVSKPNGPLADLQSLLQ SGAQVRMVDMQKLTHGVLHTKFWWDQTHFYLGSANMDWRSLTQVKELGVVMYNCSCLAR DLTKIFEAYWFLGQAGSSIPSTWPRPFDTRYNQETPMEICLNGTPALAYLASAPPPLCPG GRTPDLKALLSWDNARSFIYIAVMNYLPTMEFSHPRRFWPAIDDGLRRAAYERGVKVRL LISCWGHSEPSMRSFLLSLAALRDNHTHSDIQVKLFVVPADEAQARIPYARVNHNKYMVT ERTTYIGTSNWSGSYFTETAGTSLLVTQNGHGGLRSQLEAVFLRDWESPYSHNLDTSADS VGNACRLL

SEQ ID NO: 77 gi|31881629|reflNM_000956.2| Homo sapiens prostaglandin E receptor 2 (subtype EP2), 53kDa (PTGER2), mRNA i gccgccgtcg gcgcgctggg tgcgggaagg gggctctgga tttcggtccc tccccttttt

61 cctctgagtc tcggaacgct ccagctctca gaccctcttc ctcccaggta aaggccggga

121 gaggagggcg catctctttt ccaggcaccc caccatgggc aatgcctcca atgactccca

181 gtctgaggac tgcgagacgc gacagtggct tcccccaggc gaaagcccag ccatcagctc

241 cgtcatgttc tcggccgggg tgctggggaa cctcatagca ctggcgctgc tggcgcgccg

301 ctggcggggg gacgtggggt gcagcgccgg ccgcaggagc tccctctcct tgttccacgt

361 gctggtgacc gagctggtgt tcaccgacct gctcgggacc tgcctcatca gcccagtggt

421 actggcttcg tacgcgcgga accagaccct ggtggcactg gcgcccgaga gccgcgcgtg

481 cacctacttc gctttcgcca tgaccttctt cagcctggcc acgatgctca tgctcttcgc

541 catggccctg gagcgctacc tctcgatcgg gcacccctac ttctaccagc gccgcgtctc

601 gcgctccggg ggcctggccg tgctgcctgt catctatgca gtctccctgc tcttctgctc

661 gctgccgctg ctggactatg ggcagtacgt ccagtactgc cccgggacct ggtgcttcat

721 ccggcacggg cggaccgctt acctgcagct gtacgccacc ctgctgctgc ttctcattgt

781 ctcggtgctc gcctgcaact tcagtgtcat tctcaacctc atccgcatgc accgccgaag

841 ccggagaagc cgctgcggac cttccctggg cagtggccgg ggcggccccg gggcccgcag

901 gagaggggaa agggtgtcca tggcggagga gacggaccac ctcattctcc tggctatcat

961 gaccatcacc ttcgccgtct gctccttgcc tttcacgatt tttgcatata tgaatgaaac

1021 ctcttcccga aaggaaaaat gggacctcca agctcttagg tttttatcaa ttaattcaat

1081 aattgaccct tgggtctttg ccatccttag gcctcctgtt ctgagactaa tgcgttcagt

1141 cctctgttgt cggatttcat taagaacaca agatgcaaca caaacttcct gttctacaca

1201 gtcagatgcc agtaaacagg ctgacctttg aggtcagtag tttaaaagtt cttagttata

1261 tagcatctgg aagatcattt tgaaattgtt ccttggagaa atgaaaacag tgtgtaaaca

1321 aaatgaagct gccctaataa aaaggagtat acaaacattt aagctgtggt caaggctaca

1381 gatgtgctga caaggcactt catgtaaagt gtcagaagga gctacaaaac ctaccctcag

1441 tgagcatggt acttggcctt tggaggaaca atcggctgca ttgaagatcc agctgcctat

1501 tgatttaagc tttcctgttg aatgacaaag tatgtggttt tgtaatttgt ttgaaacccc

1561 aaacagtgac tgtactttct attttaatct tgctactacc gttatacaca tatagtgtac 1621 agccagacca gattaaactt catatgtaat ctctaggaag tcaatatgtg gaagcaacca 1681 agcctgctgt cttgtgatca cttagcgaac cctttatttg aacaatgaag ttgaaaatca 1741 taggcacctt ttactgtgat gtttgtgtat gtgggagtac tctcatcact acagtattac 1801 tcttacaaga gtggactcag tgggttaaca tcagttttgt ttactcatcc tccaggaact 1861 gcaggtcaag ttgtcaggtt atttatttta taatgtccat atgctaatag tgatcaagaa 1921 gactttagga atggttctct caacaagaaa taatagaaat gtctcaaggc agttaattct 1981 cattaatact cttattatcc tatttctggg ggaggatgta cgtggccatg tatgaagcca 2041 aatattaggc ttaaaaactg aaaaatctgg ttcattcttc agatatactg gaaccctttt 2101 aaagttgata ttggggccat gagtaaaata gattttataa gatgactgtg ttgtaccaaa 2161 attcatctgt ctatatttta tttagggaac atggtttgac tcatcttata tgggaaacca 2221 tgtagcagtg agtcatatct taatatattt ctaaatgttt ggcatgtaaa tgtaaactca 2281 gcatcaaaat atttcagtga atttgcactg tttaatcata gttactgtgt aaactcatct 2341 gaaatgttac aaaaataaac tataaaacaa aaatttgaaa aaaaaaaaaa aaaaa

SEQ ID NO: 78

Amino acid sequence of human PTGER2 encoded by the DNA sequence shown in SEQ ID NO: 77.

MGNASNDSQSEDCETRQWLPPGESPAISSVMFSAGVLGNLIALALLARRWRGDVGCSAGR RSSLSLFHVLVTELVFTDLLGTCLISPVVLASYARNQTLVALAPESRACTYFAFAMTFES LATMLMLFAmLERYLSIGHPYFYQRRVSRSGGLAVLPVIYAVSLLFCSLPLLDYGQYVQ YCPGTWCFIRHGRTAYLQL YATLLLLLIVSVLACNFSVILNLIRMHRRS RRSRCGPSLGS GRGGPGARRRGERVSMAEETDHLILLAIMTITFAVCSLPFTIFAYMNETSSRKEKWDLQA LRFLSINSI IDPWVFAILRPPVLRLMRSVLCCRISLRTQDATQTSCSTQSDASKQADL

SEQ ID NO: 79 gi|31560647|reflNM_008964.2| Mus musculus prostaglandin E receptor 2 (subtype EP2) (Ptger2), mRNA i ggtgtgtgtc tgccctgcct ggccccacgg cagcagctcg caagcaatct aaattgcttt

61 cctggattcc actactggac ttgccccctg aaggcgctgg agggagcagc tgctctggca

121 agcaccccct gctagggcag gtgaggcaca gaagcaccga gagcgaccgg atattgtagt

181 gaagaggcca ctgtacgtac aggcaggaga cccaaacaag tctgtccttg gtgcgagttg

241 ggggccggaa gggagctctg gatttcggtc cctccccttt tccctgctct gtcttggagc

301 cctggggcca tcagaccctc cgactgtctg gtacttgcct ggaagagata tcatctctcc

361 tccacaccct ccaccatgga caattttctt aatgactcca agctaatgga ggactgcaag

421 agtcgtcagt ggctcctttc gggggaaagc ccagccatca gctcggtgat gttctcggcc

481 ggggttctgg ggaatctcat cgcactggca ctgttggcgc gccgctggcg tggggacacc

541 gggtgtagcg ccggcagcag gacctctatc tccttgtttc acgtgctggt aacggaattg

601 gtgctcactg acctgctggg aacctgcctc atcagcccgg tggtgctggc ttcatattca

661 agaaaccaga ccctggtggc cctggctcGc gaaagtcacg cgtgtaccta tttcgctttc

721 actatgacct tctttagtct ggccacgatg ctcatgctct tcgctatggc cctggaacgc

781 tacctctcca tcgggtaccc ttacttctac aggcgccact tatcgcgccg cgggggtctg

841 gcggtgctgc ctgtcatcta tggggcctcc ttgctcttct gttccctgcc gctgctcaac

901 tacggggagt acgtccagta ctgtcctggg acatggtgct ttatccggca cgggaggact

961 gcataccttc agctgtacgc cacgatgctc ctgctgctta tcgtggctgt gctcgcctgc

1021 aacatcagcg ttatcctcaa cctcattcgc atgcaccgtc ggagcagaag aagccgctgc

1081 ggattgtctg gcagtagcct aagaggccct ggatctcgca ggagaggaga gaggacttcg

1141 atggcagagg agacggacca cctcattctc ctggccatta tgaccatcac cttcgccata

1201 tgctccttgc ctttcacaat ctttgcctac atggatgaaa cctcttccct aaaggaaaag

1261 tgggacctcc gagctcttcg gtttttatca gttaactcta taattgaccc ttgggtcttt

1321 gccatactta ggccaccggt cctgaggtta atgcgctcag tcctctgttg tcggacttca

1381 ctgagaacac aagaagctca gcaaacatcc tgttctaccc agtccagtgc cagtaaacag

1441 actgaccttt gtggacagtt gtgaggatgc gcttcatgag ggaacctctg aagaagtctt

1501 taaatggcct cattggagaa gtgtaagggg ctggaatata aacagaataa ccttgccctg 1561 agaagcagat gaaacagact ttatgaggta gtttgggctg cagatgtgat gacagagccc 1621 tttgtggaaa gtgtcagagg atataaagtt cacattatgt gacctttgaa ggacaatcgg 1681 ctgcgtctaa gacccagttg atttaagctt tcctgttgag tgacaaagca tgtggttttg 1741 taatttgttt taaaatgcta catggttact gttttaattt tgatgtcact gctgttataa 1801 atgcaatcag accaaatgaa attcattctc taggaagtca actcatgcaa gcgatgaagc 1861 aaccagagca gacaagttgc tgtctcgtga ttgcttaatg gactctttat ttggaccatg 1921 aagttgaatg ccattggccc cttttactgt gcgcgttcat gtgggagtcc tctctggtaa 1981 cgaaaggatg cactgatttg gttaatgcta gttaatcctt taggagctct gtcatgttgt 2041 cagattattt attctgtctt gtctattgtg ataaggctac tgaagaaaac ttcagaaatt 2101 tgcgtctcac aaaggaataa ttaaaaaaat caattttaat tagtgttctt cagttttttt 2161 atagaggaag agttttcaca gttgtatctg agatcagatt ttaggatcaa actctgaaaa 2221 ttcaagtcta tttttcaggt tctctagaat ccttctagtg ttggtactag acataactaa 2281 catacacata cactacaaga tgtttgattg tgccacggca aacgcttttg tctgtatttt 2341 tattgaggga acatattttg attcatacaa cagaagaaat catgtaactg tgagtcatat 2401 cttatatttc caaacgtttg gcatggtata aactcagcat taaagtattc cagtgagcgt 2461 gtacatttag tcagttatag tgtaaacaca tctgaaatgt tacaagctaa attataaaac 2521 aaaaaagtag aagtcttcaa tgaattaact ccccaaggac agtttgcagt taatgtagac 2581 atggcatctt ttaggtaaaa taaaagtttt taaaaaatc

SEQIDNO: 80 AminoacidsequenceofmousePTGER2 encodedbytheDNAsequenceshowninSEQID NO: 79.

MDNFLNDSKLMEDCKSRQWLLSGESPAISSVMFSΆGVLGNLIALALLARRWRGDTGCSΆG SRTSISLFHVLVTELVLTDLLGTCLISPVVLASYSRNQTLVALAPESHACTYFAFTMTFF SLATMLMLFAMALERYLSIGYPYFYRRHLSRRGGLAVLPVIYGASLLFCSLPLLNYGEYV QYCPGTWCFIRHGRTAYLQLYATMLLLLIVAVLACNISVILNLIRMHRRSRRSRCGLSGS SLRGPGSRRRGERTSMAEETDHLILLAIMTITFAICSLPFTIFAYMDETSSLKEKWDLRA LRFLSVNSIIDPWVFAILRPPVLRLMRSVLCCRTSLRTQEAQQTSCSTQSSASKQTDLCG

QL

SEQ ID NO: 81 gi|13592030|ref|NM_031088.1| Rattus norvegicus prostaglandin E receptor EP2 subtype (Ptger2), mRNA i cctgcctgga ggagagacca tctctcctca acgccctcca ccatggacaa ttctttcaat

61 gactccaggc gagtggagaa ctgcgagagt cgtcagtatc tcctttcgga cgaaagccca

121 gccatcagct cggtgatgtt cacggccggg gttctgggaa acctcatcgc gctggcactg

181 ttggcgcgcc gctggcgtgg ggacacgggg tgtagcgccg gcagcaggac ctctatctcc

241 ttgttccacg tgctggtaac ggaactggtg ctcaccgacc tgctggggac ctgcctcata

301 agcccggtgg tgctggcttc ttattcgaga aaccagaccc tagtggccct ggctcccgaa

361 agccgcgcgt gtacctattt cgctttcact atgaccttct ttagtctggc cacgatgctc

421 atgctcttcg ccatggccct ggaacgctac ctcgccatcg gacaccctta cttctacagg

481 cgccgcgtct ctcgccgcgg gggtttggcg gtgctgcctg ccatctatgg ggtctccttg

541 ctcttctgtt ctctgccgct gctcaactac ggggagtacg tccagtactg tcctgggacg

601 tggtgcttta tccagcacgg gaggaccgca taccttcagc tgtacgccac ggtgctcctg

661 ctgctcatcg tggctgtgct cggctgcaac atcagtgtga tcctcaacct tattcgcatg

721 cagcttcgga gcaaaagaag ccgctgcgga ttgtctggca gtagcctgag aggccccggg

781 tctcgccgga gaggagaaag gacttctatg gcggaggaga cggaccacct cattctcctg

841 gccattatga ccatcacctt cgctgtatgc tccctgcctt tcacaatctt tgcttatatg

901 gatgaaacct cttcccgaaa ggaaaagtgg gacctccgag ctcttagatt tttatcagtg

961 aactccataa ttgatccttg ggtttttgfc atccttagac caccagtcct gagactaatg

1021 cgctcagtcc tctgttgtcg gacttcactg agagcaccgg aagctccagg agcttcctgt

1081 tcgacccagc agacggacct ctgcggacag ttgtgagcat gcgctgcttg agggaacctg

1141 ggccaaagcc tttaaatggc ctcgttggag gaacgtaaag ggccggaatg taaacaaatg

1201 gccttgcttt gagaaaccag atgcagaaga ctttaacgag gtggttgggg ctgcacacgt 1261 gatgacgtga tgacggggcc ctttgtggta agtgtcagag gatgcataaa gttcacatcg 1321 ggtggccttt gagggacaac cagctgcatc taagacccag

SEQ ID NO: 82

Amino acid sequence of rat PTGER2 encoded by the DNA sequence shown in SEQ ID NO: 81.

MDNSFNDSRRVENCESRQYLLSDESPAISSVMFTAGVLGNLIALALLARRWRGDTGCSAG SRTSISLFHVLVTELVLTDLLGTCLISPVVLASYSRNQTLVALAPESRACTYFAFTMTFF SLATMLMLFAMALERYLAIGHPYFYRRRVSRRGGLAVLPAIYGVSLLFCSLPLLNYGEYV QYCPGTWCFIQHGRTAYLQLYATVLLLLIVAVLGCNISVILNLIRMQLRSKRSRCGLSGS SLRGPGSRRRGERTSMAEETDHLILLAIMTITFAVCSLPFTIFAYMDETSSRKEKWDLRA LRFLSVNSIIDPWVFVILRPPVLRLMRSVLCCRTSLRAPEAPGASCSTQQTDLCGQL

SEQ ID NO: 83 gi]38505171|ref]NM_000957.2| Homo sapiens prostaglandin E receptor 3 (subtype EP3) (PTGER3), transcript variant 1, mRNA i accagaggtt tcccagagag gaaggcgtgg ctccctcccg ggccagtgag ccctggcgcc

61 gccgcggccg cggtcccagc agcggagtag ggcggcggct gcgccccgca ccatgggggg

121 cagcccagcc ccagccgcgg taaacgccga cctccgccgc cgcccgcgcc gcgtctgccc

181 cctcccgctg cggctctctg gacgccatcc cctcctcacc tcgaagccaa catgaaggag

241 acccggggct acggagggga tgcccccttc tgcacccgcc tcaaccactc ctacacaggc

301 atgtgggcgc ccgagcgttc cgccgaggcg cggggcaacc tcacgcgccc tccagggtct

361 ggcgaggatt gcggatcggt gtccgtggcc ttcccgatca ccatgctgct cactggtttc

421 gtgggcaacg cactggccat gctgctcgtg tcgcgcagct accggcgccg ggagagcaag

481 cgcaagaagt ccttcctgct gtgcatcggc tggctggcgc tcaccgacct ggtcgggcag

541 cttctcacca ccccggtcgt catcgtcgtg tacctgtcca agcagcgttg ggagcacatc

601 gacccgtcgg ggcggctctg cacctttttc gggctgacca tgactgtttt cgggctctcc

661 tcgttgttca tcgccagcgc catggccgtc gagcgggcgc tggccatcag ggcgccgcac

721 tggtatgcga gccacatgaa gacgcgtgcc acccgcgctg tgctgctcgg cgtgtggctg

781 gccgtgctcg ccttcgccct gctgccggtg ctgggcgtgg gccagtacac cgtccagtgg

841 cccgggacgt ggtgcttcat cagcaccggg cgagggggca acgggactag ctcttcgcat

901 aactggggca accttttctt cgcctctgcc tttgccttcc tggggctctt ggcgctgaca

961 gtcacctttt cctgcaacct ggccaccatt aaggccctgg tgtcccgctg ccgggccaag

1021 gccacggcat ctcagtccag tgcccagtgg ggccgcatca cgaccgagac ggccattcag

1081 cttatgggga tcatgtgcgt gctgtcggtc tgctggtctc cgctcctgat aatgatgttg

1141 aaaatgatct tcaatcagac atcagttgag cactgcaaga cacacacgga gaagcagaaa

1201 gaatgcaact tcttcttaat agctgttcgc ctggcttcac tgaaccagat cttggatcct

1261 tgggtttacc tgctgttaag aaagatcctt cttcgaaagt tttgccagat gagaaaaaga

1321 agactcagag agcaagctcc tcttcttccc acctctactg tgattgatcc ttcaaggttc

1381 tgtgctcagc ccttccgttg gttcttggat ttgtcctttc ccgccatgtc ttcatcacat

1441 ccacaacttc cactaacact tgcgagcttc aaacttctta gagaaccctg cagtgtccag

1501 ctaagctgat gacttgaaga taaatctgcc taaccctggg atgaagtatc tgtgaactat

1561 tttgacagca gatgaggaat tttggggaaa ttaaaacctg cctttctgcc aggatcacat

1621 cactggaagc tccatgactc tctttttgta aaagaaaaaa aaatcacaga aacacccacG

1681 tcccaaacta ttctctttta cttcttcccc caagcccacc cccaaatata actgttatcc

1741 agaagctgtt atgtcctgtt tccatacatg tttttgtact tttactatat ctacatacat

1801 caattaaact tatgtcctat tgttttgtga atttatattt gcgtatacat tatcatatgt

1861 aaaatttgca tttttttatt gaaaattatg tttcttgaga tttatccaca ttgaaacatg

1921 gagctctaaa tcgttaattt taaccgctat agagtattcc ataatttgaa taaagcataa

1981 tttgtttgta caatctcccg ccaagggaaa attatttcca cactcatcat gacaaggagc

2041 actgcaaaaa taaaaataaa aattacattc atacatgttt aa SEQIDNO: 84 Amino acid sequence of human PTGER3 encoded by the DNA sequence shown in SEQ DD NO: 83.

MKETRGYGGDAPFCTRLNHSYTGMWAPERSAEARGNLTRPPGSGEDCGSVSVAFPITMLL TGFVGNALAMLLVSRSYRRRESKRKKSFLLCIGWLALTDLVGQLLTTPVVIWYLSKQRW EHIDPSGRLCTFFGLTMTVFGLSSLFIASAMAVERALAIRAPHWYASHMKTRATRAVLLG VWLAVLAFALLPVLGVGQYTVQWPGTWCFISTGRGGNGTSSSHNWGNLFFASAFAFLGLL ALTVTFSCNLATIKALVSRCRAKATASQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLI MMLKMIFNQTSVEHCKTHTEKQKECNFFLIAVRLASLNQILDPWVYLLLRKILLRKFCQM RKRRLREQAPLLPTSTVIDPSRFCAQPFRWFLDLSFPAMSSSHPQLPLTLASFKLLREPC SVQLS

SEQ ID NO: 85 gi|6755217|ref|NM_011196.1| Mus museums prostaglandin E receptor 3 (subtype EP3) (Ptger3), mRNA i gcggcgggcg atggagagca gagcctgggc tccggctgtc ccccagtgca ctctgctgct

61 atcccgcagc tgagccggga ggctccggcc ccgtgcgccc taccgtggcc ccgccactat

121 ggctagcatg tgggcgccgg agcactctgc tgaagcgcac agcaacctgt caagtactac

181 cgacgactgc ggctccgtgt ccgtggcctt tcccatcacc atgatggtca ctggcttcgt

241 gggcaacgcg ctggccatgc tgctcgtgtc gcgcagctac cggcgccgcg agagcaagcg

301 caagaagtct ttcctgctgt gcattggctg gctggcgctc accgacttag tggggcagct

361 cctgaccagc ccggtggtca tcctcgtgta cctgtcacag cgacgctggg agcagctcga

421 cccatcgggg cgtctgtgca ccttcttcgg gctaaccatg acagtgttcg ggctatcctc

481 gctcctggtg gccagcgcca tggccgtgga gcgcgccctg gccatccgtg cgccgcactg

541 gtatgccagc cacatgaaga ctcgcgccac gccggtactg ctgggcgtgt ggctgtctgt

601 gctcgccttc gcgctgctgc cggtgctggg cgtgggccgc tacagcgtgc agtggccggg

661 cacgtggtgc ttcatcagca ccgggccggc gggcaacgag acagaccctg cgcgcgagcc

721 gggcagcgtg gcctttgcct ccgccttcgc ctgcttgggc ttgctggctc tggtggtgac

781 ctttgcctgc aacctggcga ccatcaaagc cctggtgtcc cgctgtcggg ccaaagccgc

841 cgtctcgcag tccagcgccc agtggggcag aatcaccacg gagacggcca tccagctcat

901 ggggatcatg tgtgtgctgt ccgtctgttg gtcgccgcta ttgataatga tgttgaaaat

961 gatcttcaat cagatgtcgg ttgagcaatg caagacacag atgggaaagg agaaggagtg

1021 caattccttt ctaattgcag ttcgcctggc ttcgctgaac cagatcttgg atccctgggt

1081 ttatctgctg ctaagaaaga tccttcttcg gaagttctgc cagatgatga acaacctgaa

1141 gtggactttc attgcagtac ctgtttccct gggtctgaga atttcttctc ccagggaagg

1201 atgactgagt attttggatt gtatcttctt ttggcctcaa ttttaagttt tccttgccat

1261 taaacacacc gagacaagct ttcttaggat aatctgagag tctggttgtt agctggttcc

1321 tgtgaagact gaagactctg cacttgagac gggggcaaga cgacacagag cagcatggag

1381 agactcagtg cagaaatatc tccagcctca gaacctttgt ggacatggac accttcatgt

1441 attgatagtc tgactcttct aaataggtct gaaaaagcag cataagtttt taaacagtga

1501 agcatcaatg tgttgagagc aaatgttcat ctaataagcc atgagccaaa caagacaaaa

1561 agtctacatg agaggcaaga gagattctgc aaagggtatt tgtgccaaga aggtatacag

1621 taccacagag ttgtgtcctc agtgagagtg ggaaataagt ttctaattta attctaatta

1681 ctggctcctc agtaattcag gaatcgtgcc atcatttccc tgcttttaaa gggagaagtt

1741 tagctaaaga cacattccag gtgtcactaa cagttccaaa gctaggtgac taaatgttca

1801 gctagagctg ttaaaaggaa aaccagctaa ttatcattcc agtccaatgc tatttttgaa

1861 ttactatcta cttaagattt ctcataattt gtgctcaggc agcacaataa aaaggggggg

1921 gcaaaattac taagtgacag ttattctgca tctaagtctg tgactttttt atgaaataaa

1981 atgattttgt ctgtgttgaa at

SEQIDNO: 86

Amino acid sequence of mouse PTGER3 encoded by the DNA sequence shown in SEQ ID NO: 85.

MASMWAPEHSAEAHSNLSSTTDDCGSVSVAFPITMMVTGFVGNALAMLLVSRS YRRRESK RKKSFLLCIGWLALTDLVGQLLTSPWILVYLSQRRWEQLDPSGRLCTFFGLTMTVFGLS SLLVASAMAVERALAIRAPHWYASHMKTRATPVLLGVWLSVLAFALLPVLGVGRYSVQWP GTWCFISTGPAGNETDPAREPGSVAFASAFACLGLLALWTFACNLATIKALVSRCRAKA AVSQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLIMMLKMIFNQMSVEQCKTQMGKEKE CNSFLIAVRLASLNQILDPWVYLLLRKILLRKFCQMMNNLKWTFIAVPVSLGLRISSPRE

G

SEQIDNO: 87 gi|6981433|ref|NM_012704.1| Rattus norvegicus prostaglandin E receptor 3 (Ptger3), mRNA i cgccgtcctc cagcgcgctc cgctgcaacc ccgcagctga gcccagaggc tccggccctg

61 tgcgccctac cgcggccccg ccactatggc cggcgtgtgg gcgccggagc actcggttga

121 agcgcacagc aaccagtcaa gtgctgccga cggctgcggc tctgtgtccg tggccttccc

181 catcaccatg atggtcactg gcttcgtggg caacgcgctg gccatgttgc ttgtgtcgcg

241 cagctataga cgccgggaga gcaaacgcaa aaagtctttc ctgctgtgca ttggctggct

301 ggcgctcacc gacttggtgg ggcagctcct gaccagtccg gtggtcatcc tcgtgtacct

361 gtcgcagcga cgctgggagc aactcgaccc atcggggcgc ctgtgcacct tcttcgggct

421 gaccatgaca gtgttcggac tgtcctcgct cttggtggcc agcgccatgg ccgtggagcg

481 cgccctggct atccgtgcgc cgcactggta tgccagccac atgaagactc gcgccacgcg

541 cgcggtactg ctgggtgtgt ggctgtctgt gctcgccttc gcgctgctgc ctgtgctggg

601 cgtgggccgc tacagcgtgc agtggcccgg cacgtggtgc ttcatcagca ccgggccggc

661 gggcaacgag acggactctg cgcgggagcc gggcagcgtg gcctttgcct ccgccttcgc

721 ctgtctaggc ttgctggctc tggtggtgac ctttgcctgc aacctggcga ccatcaaagc

781 cctggtgtcc cgctgccggg ccaaagccgc cgcctcgcag tccagcgccc agtggggccg

841 gatcaccacg gagacggcta tccagcttat ggggatcatg tgtgtactgt ccgtctgctg

901 gtcgccgcta ttgataatga tgctgaaaat gatcttcaat cagatgtcag tagagcaatg

961 caagacgcag atgggaaagg agaaggagtg caattccttc ctaatcgccg ttcgcctggc

1021 ttcgctgaac cagatcttgg atccctgggt ttatctgctg ctaagaaaga tccttcttcg

1081 aaagttctgc cagatgatga acaacctgaa gcggagtttc attgcaatac ctgcttccct

1141 gagtatgaga atttcttccc ccagggaagg ataactgaat cattttggat tgtatcttct

1201 ttcggcctca tattttaagt tttccttgcc attaaacaca ccgagacaag ctt

SEQIDNO: 88

Amino acid sequence of rat PTGER3 encoded by the DNA sequence shown in SEQ ID NO: 87.

MAGVWAPEHSVEAHSNQSSAADGCGSVSVAFPITMMVTGFVGNALAMLLVSRSYRRRESK RKKSFLLCIGWLALTDLVGQLLTSPVVILVYLSQRRWEQLDPSGRLCTFFGLTMTVFGLS

SLLVASAMAVERALAIRAPHWYASHMKTRATRAVLLGVWLSVLAFALLPVLGVGRYSVQW

PGTWCFISTGPAGNETDSAREPGSVAFASAFACLGLLALVVTFACNLATIKALVSRCRAK

AAASQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLIMMLKMIFNQMSVEQCKTQMGKEK

ECNSFLIAVRLASLNQILDPWVYLLLRKILLRKFCQMMNNLKRSFIAIPASLSMRISSPR EG

SEQ ID NO: 89 gi|38505196|ref|NM_000958.2| Homo sapiens prostaglandin E receptor 4 (subtype EP4) (PTGER4), mRNA

1 gcgagagcgg agctccaagc ccggcagccc gagaggaaga tgaacagccc caggccagag 61 cctctggcag agtggacccc gagccgcccc caggtagcca ggagcggcct cagcggcagc

121 cgcaaactcc agtagccgcc cgtgctgccc gtggctgggg cggagggcag ccagagctgg

181 ggaccaaggc tccgcgccac ctgcgcgcac agcctcacac ctgaacgctg tcctcccgca

241 gacgagaccg gcgggcactg caaagctggg actcgtcttt gaaggaaaaa aaatagcgag 301 taagaaatcc agcaccattc ttcactgacc catcccgctg cacctcttgt ttcccaagtt

361 tttgaaagct ggcaactctg acctcggtgt ccaaaaatcg acagccactg agaccggctt

421 tgagaagccg aagatttggc agtttccaga ctgagcagga caaggtgaaa gcaggttgga

481 ggcgggtcca ggacatctga gggctgaccc tgggggctcg tgaggctgcc accgctgctg

541 ccgctacaga cccagccttg cactccaagg ctgcgcaccg ccagccacta tcatgtccac

601 tcccggggtc aattcgtccg cctccttgag ccccgaccgg ctgaacagcc cagtgaccat

661 cccggcggtg atgttcatct tcggggtggt gggcaacctg gtggccatcg tggtgctgtg

721 caagtcgcgc aaggagcaga aggagacgac cttctacacg ctggtatgtg ggctggctgt

781 caccgacctg ttgggcactt tgttggtgag cccggtgacc atcgccacgt acatgaaggg

841 ccaatggccc gggggccagc cgctgtgcga gtacagcacc ttcattctgc tcttcttcag

901 cctgtccggc ctcagcatca tctgcgccat gagtgtcgag cgctacctgg ccatcaacca

961 tgcctatttc tacagccact acgtggacaa gcgattggcg ggcctcacgc tctttgcagt

1021 ctatgcgtcc aacgtgctct tttgcgcgct gcccaacatg ggtctcggta gctcgcggct

1081 gcagtaccca gacacctggt gcttcatcga ctggaccacc aacgtgacgg cgcacgccgc

1141 ctactcctac atgtacgcgg gcttcagctc cttcctcatt ctcgccaccg tcctctgcaa

1201 cgtgcttgtg tgcggcgcgc tgctccgcat gcaccgccag ttcatgcgcc gcacctcgct

1261 gggcaccgag cagcaccacg cggccgcggc cgcctcggtt gcctcccggg gccaccccgc

1321 tgcctcccca gccttgccgc gcctcagcga ctttcggcgc cgccggagct tccgccgcat

1381 cgcgggcgcc gagatccaga tggtcatctt actcattgcc acctccctgg tggtgctcat

1441 ctgctccatc ccgctcgtgg tgcgagtatt cgtcaaccag ttatatcagc caagtttgga

1501 gcgagaagtc agtaaaaatc cagatttgca ggccatccga attgcttctg tgaaccccat

1561 cctagacccc tggatatata tcctcctgag aaagacagtg ctcagtaaag caatagagaa

1621 gatcaaatgc ctcttctgcc gcattggcgg gtcccgcagg gagcgctccg gacagcactg

1681 ctcagacagt caaaggacat cttctgccat gtcaggccac tctcgctcct tcatctcccg

1741 ggagctgaag gagatcagca gtacatctca gaccctcctg ccagacctct cactgccaga

1801 cctcagtgaa aatggccttg gaggcaggaa tttgcttcca ggtgtgcctg gcatgggcct

1861 ggcccaggaa gacaccacct cactgaggac tttgcgaata tcagagacct cagactcttc

1921 acagggtcag gactcagaga gtgtcttact ggtggatgag gctggtggga gcggcagggc

1981 tgggcctgcc cctaagggga gctccctgca agtcacattt cccagtgaaa cactgaactt

2041 atcagaaaaa tgtatataat aggcaaggaa agaaatacag tactgtttct ggacccttat

2101 aaaatcctgt gcaatagaca catacatgtc acatttagct gtgctcagaa gggctatcat

2161 catcctacaa ctcacattag agaacatcct ggcttttgag cacttttcaa acaatcaagt

2221 tgactcacgt gggtcctgag gcctgcagca cgtcggatgc taccccacta tgacagagga

2281 ttgtggtcac aacttgatgg ctgcgaagac ctaccctccg tttttctact agataggagg

2341 atggtagaag tttggctgct gtcataacat ccagagcttt gtcgtatttg gcacacagca

2401 gaggcccaga tattagaaag gctctattcc aataaactat gaggactgcc ttatggatga

2461 tttaagtgtc tcactaaagc atgaaatgtg aatttttatt gttgtacata cgatttaagg

2521 tatttaaagt attttcttct ctgtgagaag gtttattgtt aatacaaggt ataataaaat

2581 tatcgcaacc cctctccttc cagtataacc agctgaagtt gcagatgtta gatatttttc

2641 ataaacaagt tcgagtcaaa gttgaaaatt catagtaaga ttgatatcta taaaatagat

2701 ataaattttt aagagaaaga atttagtatt atcaaaggga taaagaaaaa aatactattt

2761 aagatgtgaa aattacagtc caaaatactg ttctttccag gctatgtata aaatacatag

2821 tgaaaattgt ttagtgatat tacatttatt tatccagaaa actgtgattt caggagaacc

2881 taacatgctg gtgaatattt tcaacttttt ccctcactaa ttggtacttt taaaaacata

2941 acataaattt tttgaagtct ttaataaata acccataatt gaagtgtata atataaaaaa

3001 ttttaaaaat ctaagcagct tattgtttct ctgaaagtgt gtgtagtttt actttcctaa

3061 ggaattacca agaatatcct ttaaaattta aaaggatggc aagttgcatc agaaagcttt

3121 attttgagat gtaaaaagat tcccaaacgt ggttacatta gccattcatg tatgtcagaa

3181 gtgcagaatt ggggcactta atggtcacct tgtaacagtt ttgtgtaact cccagtgatg

3241 ctgtacacat atttgaaggg tctttctcaa agaaatatta agcatgtttt gttgctcagt

3301 gtttttgtga attgcttggt tgtaattaaa ttctgagcct gatattgata tggttttaag

3361 aagcagttgt accaagtgaa attattttgg agattataat aaatatatac attcaaaaaa

3421 aaaaaaaaaa aa

SEQ ID NO: 90 Amino acid sequence of human PTGER4 encoded by the DNA sequence shown in SEQ ID NO: 89.

MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIWLCKSRKEQKETTFYTLVCG LAVTDLLGTLLVSPVTIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLA INHAYFYSHYVDKRLAGLTLFAVYASNVLFCALPNMGLGSSRLQYPDTWCFIDWTTNVTA

HAAYSYMYAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGTEQHHAAAAΆSVASRG

HPAASPALPRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLWRVFVNQLYQP SLEREVSKNPDLQAIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSG QHCSDSQRTSSAMSGHSRSFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPG MGLAQEDTTSLRTLRISETSDSSQGQDSESVLLVDEAGGSGRAGPAPKGSSLQVTFPSET LNLSEKCI

SEQ ID NO: 91 gi|6679530|reflNM_008965.11 Mus musculus prostaglandin E receptor 4 (subtype EP4) (Ptger4), niRNA i agcctctctg gctttccaag cttttttgaa agcaagatac tctgacctca gttccggaaa

61 gttggcagcc accgagcccc ggttccgaga cagcaaaagc ttgacaagtt ccgcactgcg

121 tgggaagaga ctgatggctg aggttggagg taccattcct agatcgaacc gtgagctcca

181 acgctgtgtg ttactaacca ccaccatcat gtccatcccc ggagtcaacg cgtccttctc

241 ctccactccg gagaggctga acagcccggt gaccattccc gcagtgatgt tcatcttcgg

301 ggtggtgggc aacctggtgg ccatcgtagt attgtgcaag tcgcgcaagg agcagaaaga

361 gacgaccttt tacactctag tatgtgggct ggctgtcact gaccttctgg gcaccttgtt

421 ggtaagcccg gtgaccatcg ccacatacat gaagggccag tggcccggag accaggcact

481 gtgtgactat agcaccttca tcctactttt cttcggtctg tcgggtctca gcatcatctg

541 tgccatgagc atcgagcgct acctggccat caaccacgcc tacttctaca gccactacgt

601 ggacaagcgg ctggccggcc tcacactctt cgccatctat gcatctaacg tgctgttctg

661 cgcgctgccc aacatgggcc tgggcagatc cgagcggcag tacccgggca cctggtgctt

721 catcgactgg accaccaacg taacggccta cgccgccttc tcttacatgt acgccggctt

781 cagctccttc ctcatccttg ccaccgtgct ctgcaacgtg ctggtgtgcg gcgcgctgct

841 ccgcatgcac cgccagttca tgcgccgcac ctcgttgggc acggagcagc accatgcggc

901 tgccgccgcc gcggtagctt cggtggcctg tcggggccac gctggggcct ccccagccct

961 gcagcgcctc agcgactttc gccgccgcag gagtttccgg cgcatcgcgg gtgcggagat

1021 ccagatggtc atcttactca tcgccacctc tctggtggtg ctcatctgct ccattccgct

1081 cgtggtgcga gtgttcatta accagttata tcagccaaac gtggtgaaag acatcagcag

1141 aaacccagat ttgcaggcca tcaggattgc ttctgtgaac cccatcctgg acccctggat

1201 ttacatcctt cttcggaaga ctgtgctcag taaagccata gagaagatca agtgcctctt

1261 ctgccgcatt ggcggttccg gcagagacag ctcggcccag cactgctcag agagtcggag

1321 gacatcttcc gccatgtccg gccactctcg ctccttcctc gcccgggagt taaaggagat

1381 cagcagcacg tcccagaccc tcctgtacct gccagacctg actgaaagca gcctcggagg

1441 caggaatttg cttccaggtt cgcatggcat gggcctgacc caagcagaca ccacctcgct

1501 gagaactttg cgaatttccg agacctcaga ctcctcccag ggccaggact ctgagagtgt

1561 cctgttggtg gatgaggtta gtgggagcca cagagaggag cctgcctcta aaggaaactc

1621 tctgcaagtc acattcccca gtgaaactct gaaattatct gaaaaatgta tatagtagct

1681 aaagggggaa tcttataaaa tcctgtgcaa tagacataca tagctgtact cagaagggct

1741 gtcttcatct ggactcccac tagagaacag gcgagctcct gagggctctc caaggctgca

1801 gactgaggtc cttgagtgcc caggcttgaa gcacattggc tgtcattctg atgtgactcg

1861 agattgcagt tgcaacttgg cagctttttt ctactggaca ggaagatggc agaagctacg

1921 ctattgtcat agcaaaagag ctttctattt ggcacatacc aggggtccag ctactggaag

1981 ggctctaccc caaactctga ggactacctt acagctgact taagtgtctc actaaagcat

2041 gaaatgtgaa tttttattgt tggaaatata atttaaggta tttatgttct tctctgtgag

2101 aaggtttatt gttaatacaa ggtataaaaa acacatgata tgccctctcc tgccaatata

2161 accagctaat attgtcgatg ttattttttt ttttccataa acaagttcag gccaaagtgt

2221 tgaaaacaga gtgaaactaa tatctataaa atagatataa atttttaaaa tagtttagta

2281 tcatcaaaga aaaaataagt agtatttaag atgtgaaaaa tgaacaacct aaaatatatt

2341 ttccaagcta tatataataa tgaaaaataa aaacattaca tttatttatc cagaaaactg

2401 tgattttagg attacctaac attgctggta aatattttca ac

SEQIDNO:92 Amino acid sequence of mouse PTGER4 encoded by the DNA sequence shown in SEQ ID NO: 91.

MAEVGGTIPRSNRELQRCVLLTTTIMSIPGVNASFSSTPERLNSPVTIPAVMFIFGλΛ/GN LVAIVVLCKSRKEQKETTFYTLVCGLAVTDLLGTLLVSPVTIATYMKGQWPGDQALCDYS TFILLFFGLSGLSIICAMSIERYLAINHAYFYSHYVDKRLAGLTLFAIYASNVLFCALPN MGLGRSERQYPGTWCFIDWTTNVTAYAAFSYMYAGFSSFLILATVLCNVLVCGALLRMHR QFMRRTSLGTEQHHAAAAAAVASVACRGHAGASPALQRLSDFRRRRSFRRIAGAEIQMVI LLIATSLVVLICSIPLVVRVFINQLYQPNVVKDISRNPDLQAIRIASVNPILDPWIYILL RKTVLSKAIEKIKCLFCRIGGSGRDSSAQHCSESRRTSSAMSGHSRSFLARELKEISSTS QTLLYLPDLTESSLGGRNLLPGSHGMGLTQADTTSLRTLRISETSDSSQGQDSESVLLVD EVSGSHREEPASKGNSLQVTFPSETLKLSEKCI

SEQ ID NO: 93 gi|31543523|ref]NM_032076.2| Rattus norvegicus prostaglandin E receptor 4 (subtype EP4) (Ptger4), mRNA i ccggttccga gagcggcaaa ggcttgacaa gttccgcact gagtgagaag agactgatgg

61 ctgaggttgg tggtaggtcc agaacgactg aggcctgaac cgtggggcgc accccaccct

121 acagatacca tccctagatc gaaccgtgag ctccaaagct gtgtactact gaccaccatc

181 atgtccatcc ccggagtcaa cgcgtccttc tcctccactc cggagaggtt gaacagccca

241 gtgaccattc ccgcagtgat gtttatcttc ggggtggtgg gcaacctggt ggccatcgta

301 gtattgtgca agtcgcgcaa ggagcagaag gagactacct tttacactct ggtatgtggg

361 ctggctgtca ctgacctact gggcacattg ttggtaagcc cagtgaccat cgccacatac

421 atgaagggcc agtggcccgg agaccaggca ttgtgtgact acagcacctt catcctactt

481 ttcttcggcc tgtcgggtct cagcatcatc tgtgccatga gcattgagcg ctacctggcc

541 atcaaccacg cctacttcta cagccactac gtggacaagc ggctggccgg tctcacgctc

601 ttcgccgtct atgcatctaa cgtgctcttc tgcgcactgc ccaacatggg cctgggtagg

661 tccgagcggc agtacccggg gacctggtgc ttcatcgact ggaccaccaa cgtaacggcc

721 tacgccgcct tctcttacat gtacgcgggc ttcagttcct tcctcatcct cgccaccgtg

781 ctctgcaatg tgctggtgtg cggcgcgctg ctccgcatgc tccgccagtt catgcgccgc

841 acctcgctgg gcacggagca gcaccacgcg gccgctgcag cagcggtggc ttcggtggcc

901 tgtcggggtc acgcggccgc ctccccagcc ctgcagcgcc tcagtgactt tcgccgccgc

961 aggagcttcc ggcgcatcgc gggtgcagag atccagatgg tcatcttact catcgccacc

1021 tctctggtgg tgctcatctg ctccattccg ctcgtggtgc gagtgttcat caaccagtta

1081 tatcagccaa gtgtggtgaa agacatcagc agaaacccgg atttgcaggc catcagaatt

1141 gcttctgtga accccatcct ggacccttgg atctacatcc ttcttcggaa gactgtgctc

1201 agtaaagcca tagaaaagat caagtgcctc ttctgccgca ttggtggttc tggcagagac

1261 ggttcagcac agcactgctc agagagtcgg aggacatctt ctgccatgtc tggccactcc

1321 cgctccttcc tctcgcggga gttgagggag atcagcagca cctctcacac cctcctatac

1381 ctgccagacc taactgaaag cagcctcgga ggcaagaatt tgcttccagg tacgcatggc

1441 atgggcctga cccaagcaga caccacctcg ctgagaactt tgcgaatttc agagacctca

1501 gactcctccc agggccagga ctctgagagt gtcttgttgg tggatgaggt tagtgggagc

1561 cagagagagg agcctgcctc taaggggaac tctctgcaag tcacgttccc cagtgaaacg

1621 ctgaaattat ctgaaaaatg tatatagtag cttaaagg

SEQ ID NO: 94

Amino acid sequence of rat PTGER4 encoded by the DNA sequence shown in SEQ ID NO: 93;

MSIPGVNASFSSTPERLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVCG LAVTDLLGTLLVSPVTIATYMKGQWPGDQALCDYSTFILLFFGLSGLSIICAMSIERYLA INHAYFYSHYVDKRLAGLTLFAVYASNVLFCALPNMGLGRSERQYPGTWCFIDWTTNVTA YAAFSYMYAGFSSFLILATVLCNVLVCGALLRMLRQFMRRTSLGTEQHHAAAAAAVASVA CRGHAAASPALQRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFINQL YQPSWKDISRNPDLQAIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSGRD GSAQHCSESRRTSSAMSGHSRSFLSRELREISSTSHTLLYLPDLTESSLGGKNLLPGTHG MGLTQADTTSLRTLRISETSDSSQGQDSESVLLVDEVSGSQREEPASKGNSLQVTFPSET LKLSEKCI

SEQ ID NO: 95 gi|8051632|ref]NM_002889.2| Homo sapiens retinoic acid receptor responder (tazarotene induced) 2 (RARRES2), mRNA

1 gcgggacggt caggggagac ctccaggcgc agggaaggac ggccagggtg acacggaagc 61 atgcgacggc tgctgatccc tctggccctg tggctgggtg cggtgggcgt gggcgtcgcc 121 gagctcacgg aagcccagcg ccggggcctg caggtggccc tggaggaatt tcacaagcac 181 ccgcccgtgc agtgggcctt ccaggagacc agtgtggaga gcgccgtgga cacgcccttc 241. ccagctggaa tatttgtgag gctggaattt aagctgcagc agacaagctg ccggaagagg 301 gactggaaga aacccgagtg caaagtcagg cccaatggga ggaaacggaa atgcctggcc 361 tgcatcaaac tgggctctga ggacaaagtt ctgggccggt tggtccactg ccccatagag 421 acccaagttc tgcgggaggc tgaggagcac caggagaccσ agtgcctcag ggtgcagcgg 481 gctggtgagg acccccacag cttctacttc cctggacagt tcgccttctc caaggccctg 541 ccccgcagct aagccagcac tgagctgcgt ggtgcctcca ggaccgctgc gggtggtaac 601 cagtggaaga ccccagcccc cagggagagg aacccgttct atccccagcc atgataataa 661 agctgctctc ccaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa

721 aaaaaaaaaa aaaa SEQIDNO: 96

Amino acid sequence of human RARRES2 encoded by the DNA sequence shown in SEQ ID NO: 95.

MRRLLIPLALWLGAVGVGVAELTEAQRRGLQVALEEFHKHPPVQWAFQETSVESAVDTPF PAGIFVRLEFKLQQTSCRKRDWKKPECKVRPNGRKRKCLACIKLGSEDKVLGRLVHCPIE TQVLREAEEHQETQCLRVQRAGEDPHSFYFPGQFAFSKALPRS

SEQ ID NO: 97

Amino acid sequence of human RARRES2, a soluble active secreted form derived from SEQ ID NO:96.

ELTEAQRRGLQVALEEFHKHPPVQWAFQETSVESAVDTPFPAGIFVRLEFKLQQTSCRKR DWKKPECKVRPNGRKRKCLACIKLGSEDKVLGRLVHCPIETQVLREAEEHQETQCLRVQR AGEDPHSFYFPGQF

SEQ ID NO: 98 gi|21313657|ref|NM_027852.1| Mus musculus retinoic acid receptor responder (tazarotene induced) 2 (Rarres2), mRNA 1 caacaactgc cagggagctg ttccagggac cacacagaaa aaggcctcgc taaagcaaca

61 aacctgatca ttttcaagaa ccataggact gaggtgaagc catgaagtgc ttgctgatct

121 ccctagccct atggctgggc acagtgggca cacgtgggac agagcccgaa ctcagcgaga

181 cccagcgcag gagcctacag gtggctctgg aggagttcca caaacaccca cctgtgcagt

241 tggccttcca agagatcggt gtggacagag ctgaagaagt gctcttctca gctggcacct 301 ttgtgaggtt ggaatttaag ctccagcaga ccaactgccc caagaaggac tggaaaaagc 361 cggagtgcac aatcaaacca aacgggagaa ggcggaaatg cctggcctgc attaaaatgg 421 accccaaggg taaaattcta ggccggatag tccactgccc aattctgaag caagggcctc 481 aggatcctca ggagttgcaa tgcattaaga tagcacaggc tggcgaagac ccccacggct 541 acttcctacc tggacagttt gccttctcca gggccctgag aaccaaataa gccctagaca 601 ggacttcacc ttactccctg tacagctgtg gcagcaccca gcaggagcat atcgtctccc 661 agagactttc aactccaggc taataaaatt gctgagtctg ttcctttcc

SEQIDNO:99

AminoacidsequenceofmouseRARRES2encodedbytheDNAsequenceshowninSEQDD NO: 98.

MKCLLISLALWLGTVGTRGTEPELSETQRRSLQVALEEFHKHPPVQLAFQEIGVDRAEEV LFSAGTFVRLEFKLQQTNCPKKDWKKPECTIKPNGRRRKCLΆCIKMDPKGKILGRIVHCP ILKQGPQDPQELQCIKIAQAGEDPHGYFLPGQFAFSRALRTK

SEQE)NO: 100 gj|34855835|ref|XM_216142.2| Rattus norvegicus similar to CHO functionally unknown type II transmembrane protein (LOC297073), mRNA

1 ggtcagtggg gaaaggcggg gctttgggga ccaagagaga ggagaaaagg gagatgagag

61 ggtgagaggg aacagttgtc agggaactgt tcgaggaacc acacagaaaa gggcctctct

121 aaagcaacga acctgatatt tttcaaggac cataggacta aagcaaagcc atgaagtgcc 181 tgctgatctc cctggcccta tggctgggca cagcggacat acacgggaca gagcttgagc 241 tcagcgagac acagcgcaga ggcctgcagg tggctctgga ggagttccac agacacccgc 301 ctgtgcagtg ggccttccag gagatcggtg tggacagtgc tgatgacctg ttcttctcag 361 ctggcacctt tgtgaggctg gaatttaagc tccagcagac cagctgcctg aagaaggact 421 ggaaaaagcc agagtgtaca atcaaaccaa atgggaggaa gcggaaatgc ctggcctgca 481 tcaaactgga ccccaagggt aaagttctag gccggatggt ccactgccca atactgaagc 541 aagggcctca gcaggagcct caggaatccc agtgcagtaa gatagcacag gccggcgagg 601 actcccgcat ctacttcttc cctgggcagt ttgccttctc cagggctcta caatccaaat 661 aagccctgga cagggtttca tcttacttcc tgtacagccg tggcggtacc caccatatgg 721 cctcccaaag actttcaact ccaggctaat aaaactgttc ctttcc SEQIDNO: 101

Amino acid sequence of rat RARRES2 encoded by the DNA sequence shown in SEQ ID NO: 100.

MKCLLISLALWLGTADIHGTELELSETQRRGLQVALEEFHRHPPVQWAFQEIGVDSADDL FFSAGTFVRLEFKLQQTSCLKKDWKKPECTIKPNGRKRKCLACIKLDPKGKVLGRMVHCP ILKQGPQQEPQESQCSKIAQAGEDSRIYFFPGQFAFSRALQSK

SEQIDNO: 102 gi|24308405|ref]NM_l38355.11Homosapienssecernin2(Ses2),mRNA

1 ggcacgaggg gcacccggga ccgagctggg gtcttggagg aagagaggat ggcgtcgtcg 61 agccctgact ccccatgttc ctgcgactgc tttgtctccg tgcccccggc ctcagccatc 121 ccggctgtga tctttgccaa gaactcggac cgaccccggg acgaggtgca ggaggtggtg 181 tttgtccccg caggcactca cactcctggg agccggctcc agtgcaccta cattgaagtg 241 gaacaggtgt cgaagacgca cgctgtgatt ctgagccgtc cttcttggct atggggggct 301 gagatgggcg ccaacgagca tggtgtctgc attggcaacg aggctgtgtg gacgagggag 361 ccagttgggg agggggaagc cctgctgggc atggacctac tcaggctggc tttggaacgg 421 agcagctctg cccaggaggc cttgcatgtg atcacagggt tactggagca ctatgggcag 481 gggggcaact gcctggagga tgctgcgcca ttctcctacc atagcacctt cctgctggct 541 ga'ccgcactg aggcgtgggt gctggagaca gctgggaggc tctgggctgc acagaggatc 601 caggaggggg cccgcaacat ctccaaccag ctgagcattg gcacggacat ctcggcccaa 661 cacccggagc tgcggactca tgcccaggcc aagggctggt gggatgggca gggtgccttt 721 gactttgctc agatcttctc cctgacccag cagcctgtgc gcatggaggc tgccaaggcc

781 cgcttccagg cagggcggga gctgctgcgg caacggcaag ggggcatcac ggcagaggtg

841 atgatgggca tcctcagaga caaggagagt ggtatctgta tggactcggg aggctttcgc

901 accacggcca gcatggtgtc tgtcctgccc caggatccca cgcagccctg cgtgcacttt

961 cttaccgcca cgccagaccc atccaggtct gtgttcaaac ctttcatctt cggggtgggg

1021 gtggcccagg ccccccaggt gctgtccccc acttttggag cacaagaccc tgttcggacc

1081 ctgccccgat tccagactca ggtagatcgt cggcataccc tctaccgtgg acaccaggca

1141 gccctggggc tgatggagag agatcaggat cgggggcagc agctccagca gaaacagcag

1201 gatctggagc aggaaggcct cgaggccaca caggggctgc tggccggcga gtgggcccca

1261 cccctctggg agctgggcgg cctcttccag gccttcgtga agagggagag ccaggcttat

1321 gcgtaagctt catagcttct gctggcctgg ggtggaccca ggacccctgg ggcctgggtg

1381 ccctgagtgg tggtaaagtg gagcaatccc ttcacgctcc ttggccatgt tctgagcggc

1441 cagcttggcc tttgccttaa taaatgtgct ttattttcaa aaaaaaaaaa aaaaaaa

SEQIDNO: 103

Amino acid sequence of human SCRN2 encoded by the DNA sequence shown in SEQ ID NO: 102.

MASSSPDSPCSCDCFVSVPPASAIPAVIFAKNSDRPRDEVQEVVFVPAGTHTPGSRLQCT YIEVEQVSKTHAVILSRPSWLWGAEMGANEHGVCIGNEAVWTREPVGEGEALLGMDLLRL ALERSSSAQEALHVITGLLEHYGQGGNCLEDAAPFSYHSTFLLADRTEAWVLETAGRLWA AQRIQEGARNISNQLSIGTDISAQHPELRTHAQAKGWWDGQGAFDFAQIFSLTQQPVRME AAKARFQAGRELLRQRQGGITAEVMMGILRDKESGICMDSGGFRTTASMVSVLPQDPTQP CVHFLTATPDPSRSVFKPFIFGVGVAQAPQVLSPTFGAQDPVRTLPRFQTQVDRRHTLYR GHQAALGLMERDQDRGQQLQQKQQDLEQEGLEATQGLLAGEWAPPLWELGGLFQAFVKRE SQAYA

SEQIDNO: 104 gi|22122498|reflNM_146027.1|Musmusculussecernin2(Scrn2),mRNA i ccacgcgtcc gctgacctga agaggaggaa gtggcgcccg gaaccgagcc tgggggtctt

61 ggatgcagag aggatggcgt cgtcgagccc cgatgcccct tgttcctgcg actgttttgt

121 ctctgtgccc ccggcctcag ccatcccagc tgtaatcttt gcaaagaact cagaccggcc

181 ccgagatgag gtgcaggagg tggtgtttat accagcaggc actcacgtcc ctgggagccg

241 gcttcagtgt acctatatcg aggtggaaca ggtggggaag acacacgctg tgattctgag

301 ccgcccctct tggctgtggg gagctgagat gggggccaac gagcttggtg tctgcattgg

361 aaacgaagca gtgtggacca aagagcctgt ggggcagggg gaagccctgc tgggtatgga

421 cctgctcagg ctggctttgg aacggagcag cactgcccag gaggctgttc acgtgattgc

481 aggcttgctg gaccgctatg ggcagggagg cagctgccgg gaggatccag agccgttctg

541 ctatcacaac acctttttac tggctgatcg gacagaggcg tgggtgctgg agacagctgg

601 gagcctgtgg gctgctcagc ggatccaggg aggtgcccgg aatatttcca accagctgag

661 cattggtaca gacatctcag ctgaacaccc ggaactccgc agccatgcca aggctcaggg

721 ttggtggact gggcagggcc tctttgactt tgcggaggtc ttctccctga cccagcagcc

781 tgtgcgcatg gaggctgcca aggcccgctt ccgggcaggg tgtgagatgc tgcagcggca

841 tcaagggaac atcacagcag aggtgatgat gggcatcctc agggacaagg agagcggcat

901 ctgcatggac tccggaggct tccgcaccac agccagtatg gtatcggtcc tgccccagga

961 tcccacaaag ccctgtgtcc acttcctcac tgccacccca gacccatcca ggtcggtatt

1021 caagcctttc atctttgaag tgggggtgtc ccagtccccc caggtgttgt cccccacttt

1081 tggagcccag gaccctgttc ggatcctccc acgattccag actcgggtgg accgtcggca

1141 ctcactctat cgtggacacc aggcagccct ggggctgatg gaggatgagc aggagcaggc

1201 acagcaactc cggaaaaagc agcagaggct ggagcaggaa ggcctagagg ctctcagagg

1261 gctgcttacg ggtgaacaga ccccaccagc ccagggcctg ggcagcctct tccaggcctt

1321 tgtggagagg gaagagcagg cctatgctta agcatgcagg agctctgggg ccggctgccc

1381 tgagctgtgg tgggtgcggt ggtggggttg agtcacagcc atcccttcac cctgctcatc

1441 caggtttgga gtgacttaat aaatgtttta tctccttctt cagtgaaaaa aaaaaaaaaa

1501 aaaaa SEQ E) NO: 105

Amino acid sequence of mouse SCRN2 encoded by the DNA sequence shown in SEQ ID NO: 104.

MASSSPDAPCSCDCFVSVPPASAIPAVIFAKNSDRPRDEVQEWFIPAGTHVPGSRLQCT YIEVEQVGKTHAVILSRPSWLWGAEMGANELGVCIGNEA¹VWTKEPVGQGEALLGMDLLRL

ALERSSTAQEAVHVIAGLLDRYGQGGSCREDPEPFCYHNTFLLADRTEAWVLETAGSLWA

AQRIQGGARNISNQLSIGTDISAEHPELRSHAKAQGWWTGQGLFDFAEVFSLTQQPVRME

AAKARFRAGCEMLQRHQGNITAEVMMGILRDKESGICMDSGGFRTTASMVSVLPQDPTKP

CVHFLTATPDPSRSVFKPFIFEVGVSQSPQVLSPTFGAQDPVRILPRFQTRVDRRHSLYR GHQAALGLMEDEQEQAQQLRKKQQRLEQEGLEALRGLLTGEQTPPAQGLGSLFQAFVERE

EQAYA

SEQIDNO: 106 ensembl|ENSRNOT00000013580cDNAtranscript

1 atggcatcat cgagccccga cgccccttgt tcctgcgact gctttgtctc tgtgcccccg 61 gcttcagcca tcccagctgt aatctttgca aagaactcag accggccccg agatgaagtc

121 caggaggtgg tgtttatacc agcaggcact cacacccctg ggagccgact tcagtgcacc

181 tacatcgagg tggaacaggt gtggaagacg catgctgtca ttctgagccg cccttcttgg

241 ctgtgggggg ctgagatggg tgccaatgag cttggtgtct gcataggcaa cgaagcggtg

301 tggaccaaag aacccgtagg ggagggggaa gccctgctgg gtatggatct actcaggctg 361 gctttggaac ggagcagtac tgcccaggcg gctgtgcacg tgattgcggg cttgctggac

421 cgctatgggc agggaggcag ctgccgggag gatccggagc ctttctgcta tcacaacacc

481 tttttactgg ctgatcggac agaggcgtgg gtgctggaga cagctgggag gctgtgggct

541 gctcagcgga tccagggagg tgcccgaaat atttccaacc aactgagcat tggaacagac

601 atctcagcag aacacccaga gctccgcagc catgccaagg ctcagggttg gtggtctggg 661 cagggcgtct ttgactttgc ggaggtcttc tccctgaccc agcagcctgt gcgcatggag

721 gctgccaagg cccgcttccg ggcagggtgt gagatgctgc agcgacaaca aggtctcatc

781 acagcagagg tgatgatgga catcctcagg aacaaggaga gcggcatctg catggactct

841 ggaggcttcc gtaccacagc cagtatggtg tcagtcctgc cccaggatcc cacaaagcct

901 tgtgttcact tcctcactgc cacaccagac ccatccaggt cggtattcaa acctttcatc 961 tttgaagtgg gggtgtccca gcccccccag gtgttgtccc ccacttttgg agcccaggac

1021 cctgttcgga tcctccccag attccagact caggtggacc gtcgacattc actgtatcgt

1081 ggacaccagg cagccctggg gctgatggac gagcaggagc aggcacaact gcggcaagag

1141 cagcagagtc tggagcagga gggcctggag gctctcagag gactgcttac tggtgaacag

1201 accccagccc cccaggagct gggcagcctc ttccaggcct ttgtggagag ggagcaccag 1261 gtctatgctt aa

SEQ K) NO: 107

Amino acid sequence of rat SCRN2 encoded by the DNA sequence shown in SEQ ID NO: 106.

MASSSPDAPCSCDCFVSVPPASAIPAVIFAKNSDRPRDEVQEWFIPAGTHTPGSRLQCT YIEVEQVWKTHAVILSRPSWLWGAEMGANELGVCIGNEAVWTKEPVGEGEALLGMDLLRL

ALERSSTAQAAVHVIAGLLDRYGQGGSCREDPEPFCYHNTFLLADRTEAWVLETAGRLWA

AQRIQGGARNISNQLSIGTDISAEHPELRSHAKAQGWWSGQGVFDFAEVFSLTQQPVRME

AAKARFRAGCEMLQRQQGLITAEVMMDILRNKESGICMDSGGFRTTASMVSVLPQDPTKP

CVHFLTATPDPSRSVFKPFIFEVGVSQPPQVLSPTFGAQDPVRILPRFQTQVDRRHSLYR GHQAALGLMDEQEQAQLRQEQQSLEQEGLEALRGLLTGEQTPAPQELGSLFQAFVEREHQ

VYA

SEQ ID NO: 108 gi|20302165|reflNM_016610.2| Homo sapiens toll-like receptor 8 (TLR8), transcript variant 1, niRNA i ctcctgcata gagggtacca ttctgcgctg ctgcaagtta cggaatgaaa aattagaaca

61 acagaaacat ggttctcttg acacttcagt gttagggaac atcagcaaga cccatcccag

121 gagaccttga aggaagcctt tgaaagggag aatgaaggag tcatctttgc aaaatagctc

181 ctgcagcctg ggaaaggaga ctaaaaagga aaacatgttc cttcagtcgt caatgctgac

241 ctgcattttc ctgctaatat ctggttcctg tgagttatgc gccgaagaaa atttttctag

301 aagctatcct tgtgatgaga aaaagcaaaa tgactcagtt attgcagagt gcagcaatcg

361 tcgactacag gaagttcccc aaacggtggg caaatatgtg acagaactag acctgtctga

421 taatttcatc acacacataa cgaatgaatc atttcaaggg ctgcaaaatc tcactaaaat

481 aaatctaaac cacaacccca atgtacagca ccagaacgga aatcccggta tacaatcaaa

541 tggcttgaat atcacagacg gggcattcct caacctaaaa aacctaaggg agttactgct

601 tgaagacaac cagttacccc aaataccctc tggtttgcca gagtctttga cagaacttag

661 tctaattcaa aacaatatat acaacataac taaagagggc atttcaagac ttataaactt

721 gaaaaatctc tatttggcct ggaactgcta ttttaacaaa gtttgcgaga aaactaacat

781 agaagatgga gtatttgaaa cgctgacaaa tttggagttg ctatcactat ctttcaattc

841 tctttcacac gtgccaccca aactgccaag ctccctacgc aaactttttc tgagcaacac

901 ccagatcaaa tacattagtg aagaagattt caagggattg ataaatttaa cattactaga

961 tttaagcggg aactgtccga ggtgcttcaa tgccccattt ccatgcgtgc cttgtgatgg

1021 tggtgcttca attaatatag atcgttttgc ttttcaaaac ttgacccaac ttcgatacct

1081 aaacctctct agcacttccc tcaggaagat taatgctgcc tggtttaaaa atatgcctca

1141 tctgaaggtg ctggatcttg aattcaacta tttagtggga gaaatagcct ctggggcatt

1201 tttaacgatg ctgccccgct tagaaatact tgacttgtct tttaactata taaaggggag

1261 ttatccacag catattaata tttccagaaa cttctctaaa cttttgtctc tacgggcatt

1321 gcatttaaga ggttatgtgt tccaggaact cagagaagat gatttccagc ccctgatgca

1381 gcttccaaac ttatcgacta tcaacttggg tattaatttt attaagcaaa tcgatttcaa

1441 acttttccaa aatttctcca atctggaaat tatttacttg tcagaaaaca gaatatcacc

1501 gttggtaaaa gatacccggc agagttatgc aaatagttcc tcttttcaac gtcatatccg

1561 gaaacgacgc tcaacagatt ttgagtttga cccacattcg aacttttatc atttcacccg

1621 tcctttaata aagccacaat gtgctgctta tggaaaagcc ttagatttaa gcctcaacag

1681 tattttcttc attgggccaa accaatttga aaatcttcct gacattgcct gtttaaatct

1741 gtctgcaaat agcaatgctc aagtgttaag tggaactgaa ttttcagcca ttcctcatgt

1801 caaatatttg gatttgacaa acaatagact agactttgat aatgctagtg ctcttactga

1861 attgtccgac ttggaagttc tagatctcag ctataattca cactatttca gaatagcagg

1921 cgtaacacat catctagaat ttattcaaaa tttcacaaat ctaaaagttt taaacttgag

1981 ccacaacaac atttatactt taacagataa gtataacctg gaaagcaagt ccctggtaga

2041 attagttttc agtggcaatc gccttgacat tttgtggaat gatgatgaca acaggtatat

2101 ctccattttc aaaggtctca agaatctgac acgtctggat ttatccctta ataggctgaa

2161 gcacatccca aatgaagcat tccttaattt gccagcgagt ctcactgaac tacatataaa

2221 tgataatatg ttaaagtttt ttaactggac attactccag cagtttcctc gtctcgagtt

2281 gcttgactta cgtggaaaca aactactctt tttaactgat agcctatctg actttacatc

2341 ttcccttcgg acactgctgc tgagtcataa caggatttcc cacctaccct ctggctttct

2401 ttctgaagtc agtagtctga agcacctcga tttaagttcc aatctgctaa aaacaatcaa

2461 caaatccgca cttgaaacta agaccaccac caaattatct atgttggaac tacacggaaa

2521 cccctttgaa tgcacctgtg acattggaga tttccgaaga tggatggatg aacatctgaa

2581 tgtcaaaatt cccagactgg tagatgtcat ttgtgccagt cctggggatc aaagagggaa

2641 gagtattgtg agtctggagc taacaacttg tgtttcagat gtcactgcag tgatattatt

2701 tttcttcacg ttctttatca ccaccatggt tatgttggct gccctggctc accatttgtt

2761 ttactgggat gtttggttta tatataatgt gtgtttagct aaggtaaaag gctacaggtc

2821 tctttccaca tcccaaactt tctatgatgc ttacatttct tatgacacca aagatgcctc

2881 tgttactgac tgggtgataa atgagctgcg ctaccacctt gaagagagcc gagacaaaaa

2941 cgttctcctt tgtctagagg agagggattg ggatccggga ttggccatca tcgacaacct

3001 catgcagagc atcaaccaaa gcaagaaaac agtatttgtt ttaaccaaaa aatatgcaaa

3061 aagctggaac tttaaaacag ctttttactt ggctttgcag aggctaatgg atgagaacat

3121 ggatgtgatt atatttatcc tgctggagcc agtgttacag cattctcagt atttgaggct

3181 acggcagcgg atctgtaaga gctccatcct ccagtggcct gacaacccga aggcagaagg

3241 cttgttttgg caaactctga gaaatgtggt cttgactgaa aatgattcac ggtataacaa

3301 tatgtatgtc gattccatta agcaatacta actgacgtta agtcatgatt tcgcgccata

3361 ataaagatgc aaaggaatga catttctgta ttagttatct attgctatgt aacaaattat 3421 cccaaaactt agtggtttaa aacaacacat ttgctggccc acagtttt SEQIDNO: 109

AminoacidsequenceofhumanTLR8encodedbytheDNAsequenceshowninSEQIDNO: 108. MKESSLQNSSCSLGKETKKENMFLQSSMLTCIFLLISGSCELCAEENFSRSYPCDEKKQN DSVIAECSNRRLQEVPQTVGKYVTELDLSDNFITHITNESFQGLQNLTKINLNHNPNVQH QNGNPGIQSNGLNITDGAFLNLKNLRELLLEDNQLPQIPSGLPESLTELSLIQNNIYNIT KEGISRLINLKNLYLAWNCYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPS SLRKLFLSNTQIKYISEEDFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFA FQNLTQLRYLNLSSTSLRKINAAWFKNMPHLKVLDLEFNYLVGEIASGAFLTMLPRLEIL DLSFNYIKGSYPQHINISRNFSKLLSLRALHLRGYVFQELREDDFQPLMQLPNLSTINLG INFIKQIDFKLFQNFSNLEIIYLSENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEFD PHSNFYHFTRPLIKPQCAAYGKALDLSLNSIFFIGPNQFENLPDIACLNLSANSNAQVLS GTEFSAIPHVKYLDLTNNRLDFDNASALTELSDLEVLDLSYNSHYFRIAGVTHHLEFIQN FTNLKVLNLSHNNIYTLTDKYNLESKSLVELVFSGNRLDILWNDDDNRYISIFKGLKNLT RLDLSLNRLKHIPNEAFLNLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNKLLF LTDSLSDFTSSLRTLLLSHNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKSALETKTTT KLSMLELHGNPFECTCDIGDFRRWMDEHLNVKIPRLVDVICASPGDQRGKSIVSLELTTC VSDVTAVILFFFTFFITTMVMLAALAHHLFYWDVWFIYNVCLAKVKGYRSLSTSQTFYDA YISYDTKDASVTDWVINELRYHLEESRDKNVLLCLEERDWDPGLAIIDNLMQSINQSKKT VFVLTKKYAKSWNFKTAFYLALQRLMDENMDVIIFILLEPVLQHSQYLRLRQRICKSSIL QWPDNPKAEGLFWQTLRNVVLTENDSRYNNMYVDSIKQY

SEQIDNO: 110 gi|45935389|ref|NM_138636.2|Homosapienstoll-likereceptor8 (TLR8),transcriptvariant2, mRNA i ctcctgcata gagggtacca ttctgcgctg ctgcaagtta cggaatgaaa aattagaaca

61 acagaaacat ggaaaacatg ttccttcagt cgtcaatgct gacctgcatt ttcctgctaa

121 tatctggttc ctgtgagtta tgcgccgaag aaaatttttc tagaagctat ccttgtgatg

181 agaaaaagca aaatgactca gttattgcag agtgcagcaa tcgtcgacta caggaagttc

241 cccaaacggt gggcaaatat gtgacagaac tagacctgtc tgataatttc atcacacaca

301 taacgaatga atcatttcaa gggctgcaaa atctcactaa aataaatcta aaccacaacc

361 ccaatgtaca gcaccagaac ggaaatcccg gtatacaatc aaatggcttg aatatcacag

421 acggggcatt cctcaaccta aaaaacctaa gggagttact gcttgaagac aaccagttac

481 cccaaatacc ctctggtttg ccagagtctt tgacagaact tagtctaatt caaaacaata

541 tatacaacat aactaaagag ggcatttcaa gacttataaa cttgaaaaat ctctatttgg

601 cctggaactg ctattttaac aaagtttgcg agaaaactaa catagaagat ggagtatttg

661 aaacgctgac aaatttggag ttgctatcac tatctttcaa ttctctttca cacgtgccac

721 ccaaactgcc aagctcccta cgcaaacttt ttctgagcaa cacccagatc aaatacatta

781 gtgaagaaga tttcaaggga ttgataaatt taacattact agatttaagc gggaactgtc

841 cgaggtgctt caatgcccca tttccatgcg tgccttgtga tggtggtgct tcaattaata

901 tagatcgttt tgcttttcaa aacttgaccc aacttcgata cctaaacctc tctagcactt

961 ccctcaggaa gattaatgct gcctggttta aaaatatgcc tcatctgaag gtgctggatc

1021 ttgaattcaa ctatttagtg ggagaaatag cctctggggc atttttaacg atgctgcccc

1081 gcttagaaat acttgacttg tcttttaact atataaaggg gagttatcca cagcatatta

1141 atatttccag aaacttctct aaacttttgt ctctacgggc attgcattta agaggttatg

1201 tgttccagga actcagagaa gatgatttcc agcccctgat gcagcttcca aacttatcga

1261 ctatcaactt gggtattaat tttattaagc aaatcgattt caaacttttc caaaatttct

1321 ccaatctgga aattatttac ttgtcagaaa acagaatatc accgttggta aaagataccc

1381 ggcagagtta tgcaaatagt tcctcttttc aacgtcatat ccggaaacga cgctcaacag

1441 attttgagtt tgacccacat tcgaactttt atcatttcac ccgtccttta ataaagccac

1501 aatgtgctgc ttatggaaaa gccttagatt taagcctcaa cagtattttc ttcattgggc

1561 caaaccaatt tgaaaatctt cctgacattg cctgtttaaa tctgtctgca aatagcaatg 1621 ctcaagtgtt aagtggaact gaattttcag ccattcctca tgtcaaatat ttggatttga 1681 caaacaatag actagacttt gataatgcta gtgctcttac tgaattgtcc gacttggaag 1741 ttctagatct cagctataat tcacactatt tcagaatagc aggcgtaaca catcatctag 1801 aatttattca aaatttcaca aatctaaaag ttttaaactt gagccacaac aacatttata 1861 ctttaacaga taagtataac ctggaaagca agtccctggt agaattagtt ttcagtggca 1921 atcgccttga cattttgtgg aatgatgatg acaacaggta tatctccatt ttcaaaggtc 1981 tcaagaatct gacacgtctg gatttatccc ttaataggct gaagcacatc ccaaatgaag 2041 cattccttaa tttgccagcg agtctcactg aactacatat aaatgataat atgttaaagt 2101 tttttaactg gacattactc cagcagtttc ctcgtctcga gttgcttgac ttacgtggaa 2161 acaaactact ctttttaact gatagcctat ctgactttac atcttccctt cggacactgc 2221 tgctgagtca taacaggatt tcccacctac cctctggctt tctttctgaa gtcagtagtc 2281 tgaagcacct cgatttaagt tccaatctgc taaaaacaat caacaaatcc gcacttgaaa 2341 ctaagaccac caccaaatta tctatgttgg aactacacgg aaaccccttt gaatgcacct 2401 gtgacattgg agatttccga agatggatgg atgaacatct gaatgtcaaa attcccagac 2461 tggtagatgt catttgtgcc agtcctgggg atcaaagagg gaagagtatt gtgagtctgg 2521 agctaacaac ttgtgtttca gatgtcactg cagtgatatt atttttcttc acgttcttta 2581 tcaccaccat ggttatgttg gctgccctgg ctcaccattt gttttactgg gatgtttggt 2641 ttatatataa tgtgtgttta gctaaggtaa aaggctacag gtctctttcc acatcccaaa 2701 ctttctatga tgcttacatt tcttatgaca ccaaagatgc ctctgttact gactgggtga 2761 taaatgagct gcgctaccac cttgaagaga gccgagacaa aaacgttctc ctttgtctag 2821 aggagaggga ttgggatccg ggattggcca tcatcgacaa cctcatgcag agcatcaacc 2881 aaagcaagaa aacagtattt gttttaacca aaaaatatgc aaaaagctgg aactttaaaa 2941 cagcttttta cttggctttg cagaggctaa tggatgagaa catggatgtg attatattta 3001 tcctgctgga gccagtgtta cagcattctc agtatttgag gctacggcag cggatctgta 3061 agagctccat cctccagtgg cctgacaacc cgaaggcaga aggcttgttt tggcaaactc 3121 tgagaaatgt ggtcttgact gaaaatgatt cacggtataa caatatgtat gtcgattcca 3181 ttaagcaata ctaactgacg ttaagtcatg atttcgcgcc ataataaaga tgcaaaggaa 3241 tgacatttct gtattagtta tctattgcta tgtaacaaat tatcccaaaa cttagtggtt 3301 taaaacaaca catttgctgg cccacagttt ttgagggtca ggagtccagg cccagcataa 3361 ctgggtcctc tgctcagggt gtctcagagg ctgcaatgta ggtgttcacc agagacatag 3421 gcatcactgg ggtcacactc atgtggttgt tttctggatt caattcctcc tgggctattg 3481 gccaaaggct atactcatgt aagccatgcg agcctctccc acaaggcagc ttgcttcatc 3541 agagctagca aaaaagagag gttgctagca agatgaagtc acaatctttt gtaatcgaat 3601 caaaaaagtg atatctcatc actttggcca tattctattt gttagaagta aaccacaggt 3661 cccaccagct ccatgggagt gaccacctca gtccagggaa aacagctgaa gaccaagatg 3721 gtgagctctg attgcttcag ttggtcatca actattttcc cttgactgct gtcctgggat 3781 ggcctgctat cttgatgata gattgtgaat atcaggaggc agggatcact gtggaccatc 3841 ttagcagttg acctaacaca tcttcttttc aatatctaag aacttttgcc actgtgacta 3901 atggtcctaa tattaagctg ttgtttatat ttatcatata tctatggcta catggttata 3961 ttatgctgtg gttgcgttcg gttttattta cagttgcttt tacaaatatt tgctgtaaca 4021 tttgacttct aaggtttaga tgccatttaa gaactgagat ggatagcttt taaagcatct 4081 tttacttctt accatttttt aaaagtatgc agctaaattc gaagcttttg gtctatattg 4141 ttaattgcca ttgctgtaaa tcttaaaatg aatgaataaa aatgtttcat tttacaaaaa 4201 aaaaaaaaaa a SEQ ID NO: 111

Amino acid sequence of human TLR8 variant ORF number 1 encoded by the DNA sequence shown in SEQ ID NO: 110.

MENMFLQSSMLTCIFLLISGSCELCAEENFSRSYPCDEKKQNDSVIAECSNRRLQEVPQT VGKYVTELDLSDNFITHITNESFQGLQNLTKINLNHNPNVQHQNGNPGIQSNGLNITDGA FLNLKNLRELLLEDNQLPQIPSGLPESLTELSLIQNNIYNITKEGISRLINLKNLYLAWN CYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPSSLRKLFLSNTQIKYISEE DFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQNLTQLRYLNLSSTSLR KINAAWFKNMPHLKVLDLEFNYLVGEIASGAFLTMLPRLEILDLSFNYIKGSYPQHINIS RNFSKLLSLRALHLRGYVFQELREDDFQPLMQLPNLSTINLGINFIKQIDFKLFQNFSNL EIIYLSENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEFDPHSNFYHFTRPLIKPQCA AYGKALDLSLNSIFFIGPNQFENLPDIACLNLSANSNAQVLSGTEFSAIPHVKYLDLTNN RLDFDNASALTELSDLEVLDLSYNSHYFRIAGVTHHLEFIQNFTNLKVLNLSHNNIYTLT DKYNLESKSLVELVFSGNRLDILWNDDDNRYISIFKGLKNLTRLDLSLNRLKHIPNEAFL NLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNKLLFLTDSLSDFTSSLRTLLLS HNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKSALETKTTTKLSMLELHGNPFECTCDI GDFRRWMDEHLNVKIPRLVDVICASPGDQRGKSIVSLELTTCVSDVTAVILFFFTFFITT MVMLAALAHHLFYWDVWFIYNVCLAKVKGYRSLSTSQTFYDAYISYDTKDASVTDWVINE LRYHLEESRDKNVLLCLEERDWDPGLAIIDNLMQSINQSKKTVFVLTKKYAKSWNFKTAF YLALQRLMDENMDVIIFILLEPVLQHSQYLRLRQRICKSSILQWPDNPKΆEGLFWQTLRN VVLTENDSRYNNMYVDSIKQY

SEQIDNO: 112 gi|18875361|ref|NM_133212.1|Musmusculustoll-likereceptor8(Tlr8),mRNA i attcagagtt ggatgttaag agagaaacaa acgttttacc ttcctttgtc tatagaacat

61 ggaaaacatg ccccctcagt catggattct gacgtgcttt tgtctgctgt cctctggaac

121 cagtgccatc ttccataaag cgaactattc cagaagctat ccttgtgacg agataaggca

181 caactccctt gtgattgcag aatgcaacca tcgtcaactg catgaagttc cccaaactat

241 aggcaagtat gtgacaaaca tagacttgtc agacaatgcc attacacata taacgaaaga

301 gtcctttcaa aagctgcaaa acctcactaa aatcgatctg aaccacaatg ccaaacaaca

361 gcacccaaat gaaaataaaa atggtatgaa tattacagaa ggggcacttc tcagcctaag

421 aaatctaaca gttttactgc tggaagacaa ccagttatat actatacctg ctgggttgcc

481 tgagtctttg aaagaactta gcctaattca aaacaatata tttcaggtaa ctaaaaacaa

541 cacttttggg cttaggaact tggaaagact ctatttgggc tggaactgct attttaaatg

601 taatcaaacc tttaaggtag aagatggggc atttaaaaat cttatacact tgaaggtact

661 ctcattatct ttcaataacc ttttctatgt gccccccaaa ctaccaagtt ctctaaggaa

721 actttttctg agtaatgcca aaatcatgaa catcactcag gaagacttca aaggactgga

781 aaatttaaca ttactagatc tgagtggaaa ctgtccaagg tgttacaatg ctccatttcc

841 ttgcacacct tgcaaggaaa actcatccat ccacatacat cctctggctt ttcaaagtct

901 cacccaactt ctctatctaa acctttccag cacttccctc aggacgattc cttctacctg

961 gtttgaaaat ctgtcaaatc tgaaggaact ccatcttgaa ttcaactatt tagttcaaga

1021 aattgcctcg ggggcatttt taacaaaact acccagttta caaatccttg atttgtcctt

1081 caactttcaa tataaggaat atttacaatt tattaatatt tcctcaaatt tctctaagct

1141 tcgttctctc aagaagttgc acttaagagg ctatgtgttc cgagaactta aaaagaagca

1201 tttcgagcat ctccagagtc ttccaaactt ggcaaccatc aacttgggca ttaactttat

1261 tgagaaaatt gatttcaaag ctttccagaa tttttccaaa ctcgacgtta tctatttatc

1321 aggaaatcgc atagcatctg tattagatgg tacagattat tcctcttggc gaaatcgtct

1381 tcggaaacct ctctcaacag acgatgatga gtttgatcca cacgtgaatt tttaccatag

1441 caccaaacct ttaataaagc cacagtgtac tgcttatggc aaggccttgg atttaagttt

1501 gaacaatatt ttcattattg ggaaaagcca atttgaaggt tttcaggata tcgcctgctt

1561 aaatctgtcc ttcaatgcca atactcaagt gtttaatggc acagaattct cctccatgcc

1621 ccacattaaa tatttggatt taaccaacaa cagactagac tttgatgata acaatgcttt

1681 cagtgatctt cacgatctag aagtgctgga cctgagccac aatgcacact atttcagtat

1741 agcaggggta acgcaccgtc taggatttat ccagaactta ataaacctca gggtgttaaa

1801 cctgagccac aatggcattt acaccctcac agaggaaagt gagctgaaaa gcatctcact

1861 gaaagaattg gttttcagtg gaaatcgtct tgaccatttg tggaatgcaa atgatggcaa

1921 atactggtcc atttttaaaa gtctccagaa tttgatacgc ctggacttat catacaataa

1981 ccttcaacaa atcccaaatg gagcattcct caatttgcct cagagcctcc aagagttact

2041 tatcagtggt aacaaattac gtttctttaa ttggacatta ctccagtatt ttcctcacct

2101 tcacttgctg gatttatcga gaaatgagct gtattttcta cccaattgcc tatctaagtt

2161 tgcacattcc ctggagacac tgctactgag ccataatcat ttctctcacc taccctctgg

2221 cttcctctcc gaagccagga atctggtgca cctggatcta agtttcaaca caataaagat

2281 gatcaataaa tcctccctgc aaaccaagat gaaaacgaac ttgtctattc tggagctaca

2341 tgggaactat tttgactgca cgtgtgacat aagtgatttt cgaagctggc tagatgaaaa

2401 tctgaatatc acaattccta aattggtaaa tgttatatgt tccaatcctg gggatcaaaa

2461 atcaaagagt atcatgagcc tagatctcac gacttgtgta tcggatacca ctgcagctgt

2521 cctgtttttc ctcacattcc ttaccacctc catggttatg ttggctgctc tggttcacca

2581 cctgttttac tgggatgttt ggtttatcta tcacatgtgc tctgctaagt taaaaggcta

2641 caggacttca tccacatccc aaactttcta tgatgcttat atttcttatg acaccaaaga

2701 tgcatctgtt actgactggg taatcaatga actgcgctac caccttgaag agagtgaaga

2761 caaaagtgtc ctcctttgtt tagaggagag ggattgggat ccaggattac ccatcattga 2821 taacctcatg cagagcataa accagagcaa gaaaacaatc tttgttttaa ccaagaaata 2881 tgccaagagc tggaacttta aaacagcttt ctacttggcc ttgcagaggc taatggatga 2941 gaacatggat gtgattattt tcatcctcct ggaaccagtg ttacagtact cacagtacct 3001 gaggcttcgg cagaggatct gtaagagctc catcctccag tggcccaaca atcccaaagc 3061 agaaaacttg ttttggcaaa gtctgaaaaa tgtggtcttg actgaaaatg attcacggta 3121 tgacgatttg tacattgatt ccattaggca atactagtga tgggaagtca cgactctgcc 3181 atcataaaaa cacacagctt ctccttacaa tgaaccgaat

SEQ ID NO: 113

AminoacidsequenceofmouseTLR8encodedbytheDNAsequenceshowninSEQIDNO: 112.

MENMPPQSWILTCFCLLSSGTSAIFHKANYSRSYPCDEIRHNSLVIAECNHRQLHEVPQT IGKYVTNIDLSDNAITHITKESFQKLQNLTKIDLNHNAKQQHPNENKNGMNITEGALLSL RNLTVLLLEDNQLYTIPAGLPESLKELSLIQNNIFQVTKNNTFGLRNLERLYLGWNCYFK CNQTFKVEDGAFKNLIHLKVLSLSFNNLFYVPPKLPSSLRKLFLSNAKIMNITQEDFKGL ENLTLLDLSGNCPRCYNAPFPCTPCKENSSIHIHPLAFQSLTQLLYLNLSSTSLRTIPST WFENLSNLKELHLEFNYLVQEIASGAFLTKLPSLQILDLSFNFQYKEYLQFINISSNFSK LRSLKKLHLRGYVFRELKKKHFEHLQSLPNLATINLGINFIEKIDFKAFQNFSKLDVIYL SGNRIASVLDGTDYSSWRNRLRKPLSTDDDEFDPHVNFYHSTKPLIKPQCTAYGKALDLS LNNIFIIGKSQFEGFQDIACLNLSFNANTQVFNGTEFSSMPHIKYLDLTNNRLDFDDNNA FSDLHDLEVLDLSHNAHYFSIAGVTHRLGFIQNLINLRVLNLSHNGIYTLTEESELKSIS LKELVFSGNRLDHLWNANDGKYWSIFKSLQNLIRLDLSYNNLQQIPNGAFLNLPQSLQEL LISGNKLRFFNWTLLQYFPHLHLLDLSRNELYFLPNCLSKFAHSLETLLLSHNHFSHLPS GFLSEARNLVHLDLSFNTIKMINKSSLQTKMKTNLSILELHGNYFDCTCDISDFRSWLDE NLNITIPKLVNVICSNPGDQKSKSIMSLDLTTCVSDTTAAVLFFLTFLTTSMVMLAALVH HLFYWDVWFIYHMCSAKLKGYRTSSTSQTFYDAYISYDTKDASVTDWVINELRYHLEESE DKSVLLCLEERDWDPGLPIIDNLMQSINQSKKTIFVLTKKYAKSWNFKTAFYLALQRLMD ENMDVIIFILLEPVLQYSQYLRLRQRICKSSILQWPNNPKAENLFWQSLKNVVLTENDSR YDDLYIDSIRQY

SEQ ID NO: 114 gi|14290559|gb|BC009052.1| Homo sapiens transmembrane 7 superfamily member 2, mRNA (cDNA clone MGC:9286 IMAGE:3874367), complete cds i caggcaggtg caggcgccgc ggggccggat cctccgcgcg gccgagtcca tctcctggga

61 aatggggcgg acagtgtttc cttgactgac tattgtgagc gccctctctc tccggcggag

121 cggagaccat ggcccccact cagggccccc gggccccgct ggaattcgga gggcccctgg

181 gcgccgcggc tctgctactg ctgctgcccg ccaccatgtt ccacctgctc ctggcggccc

241 gttcgggccc cgcgcgcctg ctgggtccac ccgcgtccct gcccgggctg gaggtgctgt

301 ggagcccacg ggcgctgctg ctgtggctcg cctggctcgg cctgcaggcg gcgctctacc

361 tactgccggc gcgcaaggtg gccgaggggc aggaattgaa ggacaagagt cgcctgcgct

421 atcctattaa cggcttccag gccctggtgc tgacagccct gttggtgggg ctggggatgt

481 cagcggggct gcctctgggg gcgctcccgg aaatgctcct gcccttggcg tttgtcgcca

541 ccctcaccgc tttcatcttc agcctttttc tctacatgaa ggcgcaggta gccccagttt

601 cggccctggc acctgggggg aactcaggca atccgattta cgactttttt ctgggacgag

661 agctcaaccc tcgtatctgt ttcttcgact tcaaatattt ctgtgaactg cgacccggcc

721 tcatcggctg ggtcctcatc aacctggccc tgttgatgaa ggaggcagag cttcgaggca

781 gtccctcact ggccatgtgg ctggtcaatg gcttccagtt gctctacgtg ggtgatgccc

841 tctggcacga ggaggccgtc ctcaccacca tggatatcac acatgacggg tttggcttca

901 tgctggcgtt tggggacatg gcctgggtgc ccttcaccta cagcctgcag gcccagttcc

961 tgctgcacca cccgcagccc ctggggttgc ccatggcctc tgtcatctgc ctcatcaatg

1021 ctactggtta ctacatcttc cgtggggcga attcccagaa aaacactttc cgaaagaatc

1081 cttctgaccc cagagtggct gggcttgaga ccatctctac agccacaggg cggaaactgc

1141 tggtgtctgg gtggtggggt atggtccgcc atcccaacta tcttggagac ctcatcatgg

1201 ctctggcttg gtccttgccc tgcggggtgt cacacctgct gccctacttc tacctcctct 1261 acttcaccgc gctgctggtg caccgtgagg cccgggatga gcggcagtgc ctgcagaagt

1321 acggcctggc ctggcaggag tactgccggc gtgtgcctta ccgcatcatg ccctacatct

1381 actgaagcgg ctccaccacc ccaggtgggg gcatgtgccc actcatccac cagcacaccc

1441 aggaccagga gcctcgacac acttgggact caagggcttg caccccaccc agccctgagg

1501 atgaacaacc tcagagaaga ggtggtttag agcaaggaaa aaaatgaaac cagtgaccaa

1561 aaaaaaaaaa aaaaaaaaaa

SEQIDNO: 115

AminoacidsequenceofhumanTM7SF2encodedbytheDNAsequenceshowninSEQID NO: 114. MAPTQGPRAPLEFGGPLGAΆALLLLLPATMFHLLLAARSGPARLLGPPASLPGLEVLWSP RALLLWLAWLGLQAALYLLPARKVAEGQELKDKSRLRYPINGFQALVLTALLVGLGMSAG LPLGALPEMLLPLAFVATLTAFIFSLFLYMKAQVAPVSALAPGGNSGNPIYDFFLGRELN PRICFFDFKYFCELRPGLIGWVLINLALLMKEAELRGSPSLAMWLVNGFQLLYVGDALWH EEAVLTTMDITHDGFGFMLAFGDMAWVPFTYSLQAQFLLHHPQPLGLPMASVICLINATG YYIFRGANSQKNTFRKNPSDPRVAGLETISTATGRKLLVSGWWGMVRHPNYLGDLIMALA WSLPCGVSHLLPYFYLLYFTALLVHREARDERQCLQKYGLAWQEYCRRVPYRIMPYIY

SEQIDNO: 116 gi|23468327|gb|BC038353.1| Homo sapiens transmembrane 7 superfamily member 2, mRNA (cDNA clone MGC:9089 IMAGE:3861907), complete cds i tgtccaggca ggtgcaggcg ccgcggggcc ggatcctccg cgcggccgag tccatctcct

61 gggaaatggg gcggacagtg tttccttgac tgactattgt gagcgccctc tctctccggc

121 ggagcggaga ccatggcccc cactcagggc ccccgggccc cgctggaatt cggagggccc

181 ctgggcgccg cggctctgct actgctgctg cccgccacca tgttccacct gctcctggcg

241 gcccgttcgg gccccgcgcg cctgctgggt ccacccgcgt ccctgcccgg gctggaggtg

301 ctgtggagcc cacgggcgct gctgctgtgg ctcgcctggc tcggcctgca ggcggcgctc

361 tacctactgc cggcgcgcaa ggtggccgag gggcaggaat tgaaggacaa gagtcgcctg

421 cgctatccta ttaacggctt ccaggccctg gtgctgacag ccctgttggt ggggctgggg

481 atgtcagcgg ggctgcctct gggggcgctc ccggaaatgc tcctgccctt ggcgtttgtc

541 gccaccctca ccgctttcat cttcagcctc tttctctaca tgaaggcgca ggtagcccca

601 gtttcggccc tggcacctgg ggggaactca ggcaatccga tttacgactt ttttctggga

661 cgagagctca accctcgtat ctgtttcttc gacttcaaat atttctgtga actgcgaccc

721 ggcctcatcg gctgggtcct catcaacctg gccctgttga tgaaggaggc agagcttcga

781 ggcagtccct cactggccat gtggctggtc aatggcttcc agttgctcta cgtgggtgat

841 gccctctggc acgaggaggc cgtcctcacc accatggata tcacacatga cgggtttggc

901 ttcatgctgg cgtttgggga catggcctgg gtgcccttca cctacagcct gcaggcccag

961 ttcctgctgc accacccgca gcccctgggg ttgcccatgg cctctgtcat ctgcctcatc

1021 aatgggcttg agaccatctc tacagccaca gggcggaaac tgctggtgtc tgggtggtgg

1081 ggtatggtcc gccatcccaa ctatcttgga gacctcatca tggctctggc ttggtccttg

1141 ccctgcgggg tgtcacacct gctgccctac ttctacctcc tctacttcac cgcgctgctg

1201 gtgcaccgtg aggcccggga tgagcggcag tgcctgcaga agtacggcct ggcctggcag

1261 gagtactgcc ggcgtgcgcc ttaccgcatc atgccctaca tctactgaag cggctccacc

1321 accccaggtg ggggcatgtg cccactcatc caccagcaca cccaggacca ggagcctcga

1381 cacacttggg actcaagggc ttgcacccca cccagccctg aggatgaaca acctcagaga

1441 agaggtggtt tagagcaagg aaaaaatgaa accagtgacc aaaatcggaa aaaaaaaaaa

1501 aaaaaaaa

SEQIDNO: 117

Amino acid sequence of human TM7SF2 variant ORF number 1 encoded by the DNA sequence shown in SEQ ID NO: 116. MAPTQGPRAPLEFGGPLGAAALLLLLPATMFHLLLAARSGPARLLGPPASLPGLEVLWSP

RALLLWLAWLGLQAALYLLPARKVAEGQELKDKSRLRYPINGFQALVLTALLVGLGMSAG

LPLGALPEMLLPLAFVATLTAFIFSLFLYMKAQVAPVSALAPGGNSGNPIYDFFLGRELN PRICFFDFKYFCELRPGLIGWVLINLALLMKEAELRGSPSLAMWLVNGFQLLYVGDALWH EEAVLTTMDITHDGFGFMLAFGDMAWVPFTYSLQAQFLLHHPQPLGLPMASVICLINGLE TISTATGRKLLVSGWWGMVRHPNYLGDLIMALAWSLPCGVSHLLPYFYLLYFTALLVHRE ARDERQCLQKYGLAWQEYCRRAPYRIMPYIY

SEQIDNO: 118 gi|4507546|ref]NM_003273.1|Homosapienstransmembrane7superfamilymember2 (TM7SF2),mRNA i cgccgcgggg ccggatcctc cgcgcggccg agtccatctc ctgggaaatg gggcggacag

61 tgtttccttg actgactatt gtgagcgccc tctctctccg gcggagcgga gaccatggcc

121 cccactcagg cccccgggcc ccgctggaat tcggagggcc cctgggtaat ggggcagaga

181 gatgggacct ggggcaaagg ctaagcgaag gagagctgga gcgggtgaac taagagcggg

241 ggcgagatct gaggatggaa ggctttgggg gtgtcggagg cagagggacc cgggggtttg

301 cagcgaaggg tgtctggaga gggagagctg aggaggggcc ggttctgggg gctgcagaac

361 ggggatttat ggtgtcgact gggagcagga ggagggtctt cgaggggcct gggggcgggg

421 gactaagatg gacgcctggg aagggaactg ggaggcagcg gggtgcctgg gggccgaggg

481 ctgaggacgg ggtgcggagg cgcactctgg gaatgccgag agggtcccgc agagacgtca

541 gggcgccgtg cgggccggcg gggagctggg gggctagggg cggacgccga cgtgatggcc

601 cttcccgcag gcgccgcggc tctgctactg ctgctgcccg ccaccatgtt ccacctgctc

661 ctggcggccc gttcgggccc cgcgcgcctg ctgggtccac ccgcgtccct gcccgggctg

721 gaggtgctgt ggagcccacg ggcgctgctg ctgtggctcg cctggctcgg cctgcaggcg

781 gcgctctacc tactgccggc gcgcaaggtg cgggccccgc tcgcggacgc tcgggggagg

841 gaagcgaatg ggctcggcga gggaaaggac gccccgggcc ttatcagagc ccccttggac

901 ccgcagtggc cgaggggcag gaattgaagg acaagagtcg cctgcgctat cctattaacg

961 gcttccaggc cctggtgctg acagccctgt tggtggggct ggggatgtca gcggggctgc

1021 ctctgggggc gctcccggaa atgctcctgc ccttggcgtt tgtcgccacc ctcaccgctt

1081 tcatcttcag cctctttctc tacatgaagg cgcaggtagc cccagtttcg gccctggcac

1141 ctggggggaa ctcaggcaat ccgatttacg acttttttct gggacgagag ctcaaccctc

1201 gtatctgttt cttcgacttc aaatatttct gtgaactgcg acccggcctc atcggctggg

1261 tcctcatcaa cctggccctg ttgatgaagg aggcagagct tcgaggcagt ccctcactgg

1321 ccatgtggct ggtcaatggc ttccagttgc tctacgtggg tgatgccctc tggcacgagg

1381 aggccgtcct caccaccatg gatatcacac atgacgggtt tggcttcatg ctggcgtttg

1441 gggacatggc ctgggtgccc ttcacctaca gcctgcaggc ccagttcctg ctgcaccacc

1501 cgcagcccct ggggttgccc atggcctctg tcatctgcct catcaatgct actggttact

1561 acatcttccg tggggcgaat tcccagaaaa acactttccg aaagaatcct tctgacccca

1621 gagtggctgg gcttgagacc atctctacag ccacagggcg gaaactgctg gtgtctgggt

1681 ggtggggtat ggtccgccat cccaactatc ttggagacct catcatggct ctggcttggt

1741 ccttgccctg cggggtgtca cacctgctgc cctacttcta cctcctctac ttcaccgcgc

1801 tgctggtgca ccgtgaggcc cgggatgagc ggagtgcctg cagaagtacg gcctggcctg

1861 gcaggagtac tgccggcgtg tgccttaccg catcatgccc tacatctact gaagcggctc

1921 caccacccca ggtggggcat gtgcccactc atccaccagc acacccagga ccaggagcct

1981 cgacacactt gggactcaag ggcttgcacc ccacccagcc ctgaggatga acaacctcag

2041 agaagaggtg gtttagagca aggaaaaaaa tgaaaccagt gaccaaaaaa aaaaaaaaaa

SEQ ID NO: 119

Amino acid sequence of human TM7SF2 variant ORF number 2 encoded by the DNA sequence shown in SEQ ID NO: 118.

MEGFGGVGGRGTRGFAAKGVWRGRAEEGPVLGAAERGFMVSTGSRRRVFEGPGGGGLRWT PGKGTGRQRGAWGPRAEDGVRRRTLGMPRGSRRDVRAPCGPAGSWGARGGRRRDGPSRRR RGSATAAARHHVPPAPGGPFGPRAPAGSTRVPARAGGAVEPTGAAAVARLARPAGGALPT AGAQGAGPARGRSGEGSEWARRGKGRPGPYQSPLGPAVAEGQELKDKSRLRYPINGFQAL VLTALLVGLGMSAGLPLGALPEMLLPLAFVATLTAFIFSLFLYMKAQVAPVSALAPGGNS GNPIYDFFLGRELNPRICFFDFKYFCELRPGLIGWVLINLALLMKEAELRGSPSLAMWLV NGFQLLYVGDALWHEEAVLTTMDITHDGFGFMLAFGDMAWVPFTYSLQAQFLLHHPQPLG LPMASVICLINATGYYIFRGANSQKNTFRKNPSDPRVAGLETISTATGRKLLVSGWWGMV RHPNYLGDLIMALAWSLPCGVSHLLPYFYLLYFTALLVHREARDERSACRSTAWPGRSTA GVCLTASCPTSTEAAPPPQVGHVPTHPPAHPGPGASTHLGLKGLHPTQP

SEQ ID NO: 120 genomic] Mus muscuhis computational transcript prediction from genomic i atgaacaaga gcagcagctt ttccacctcc gtgtctgatg cagagccata acccggcatg

61 gggcggtttg tgtttccttg atcgactttt gtgaaccatt gttccccggc aaagcagaga

121 tcatgacttc tcgtgaggcc tcccaggccc cactggaatt cggggggccg ttgggcgtcg

181 cggctttact gatcctgctg cctgccacca tgttccacct gctcctggcg gctcgctcgg

241 gcccggcgcg cctcctggcc ctaccggcct atctgcctgg gctggaggag ctgtggagcc

301 catgggctct gctgctattg ttcatctggc tcggcctgca ggtggcgctc tatttgctgc

361 ctgcacgcaa ggtggccgaa ggcctggaac tgaaggacaa gagtcgcctg cgctacccta

421 ttaatggctt ccaggctctg gtgctaacag ccctgttgat ggggctgggg gtgtcagtgg

481 ggctgcccct gggggcactc cctggaatgc tcctgccctt ggcctttgcg accactctca

541 ccagctttat cttcagcctc ctcctctatg cgaaggcttt ggtagctcct gcctcagccc

601 tggctcctgg gggaaactca ggaaattcca tgtatgactt ctttcttgga cgggagctga

661 accctcgcct cggttccttt gacttcaaat atttctgtga gctgagacct ggcctcattg

721 gctgggtttt cattaacctg gccctgctga tgcaggaggc agagcttcgg gggagtcctt

781 ccctggctat gtggctggtc aatggcttcc agttgctgta tgtgggtgat gccctctggt

841 atgaggagtc tgtcctcacc accatggaca taatacatga tggttttggc ttcatgctgg

901 tctttggaga tctagcttgg gtaccattca cctacagcct gcaggcccag ttcctgttgt

961 accatccaca gcctctgggg ttgcccatgg ccttgctcat ctgcctcctt aaggttattg

1021 gttactacat cttccgaggg gccaactccc agaaaaacac attcaggaag aatccttctg

1081 accccagcgt ggctggtctt gagaccatcc cgactgccac ggggaggcag ctgctggtgt

1141 ctgggtggtg gggtatggtt cgacacccca actacctggg agatctcatc atggctctgg

1201 catggtcttt gccctgtggg ctatcccatc tgctgcccta cttctacgtc ctctacttca

1261 ctgcactgct ggtgcaccgc gaggccagag atgagcagca gtgcctccaa aagtatggcc

1321 gtgcctggca ggagtactgc aagcgtgtgc cttaccgaat cataccctat gtctactgaa

1381 gcaggtccac ctaagaggtt gaaagcaaga ggaagccact gcttccagaa ggaaagtatt

1441 tttccctgtt gaataaatgt tttcaacctt SEQIDNO: 121

Amino acid sequence of mouse TM7SF2 encoded by the DNA sequence shown in SEQ ID NO: 120.

MTSREASQAPLEFGGPLGVAALLILLPATMFHLLLAARSGPARLLALPAYLPGLEELWSP WALLLLFIWLGLQVALYLLPARKVAEGLELKDKSRLRYPINGFQALVLTALLMGLGVSVG LPLGALPGMLLPLAFATTLTSFIFSLLLYAKALVAPASALAPGGNSGNSMYDFFLGRELN PRLGSFDFKYFCELRPGLIGWVFINLALLMQEAELRGSPSLAMWLVNGFQLLYVGDALWY EESVLTTMDIIHDGFGFMLVFGDLAWVPFTYSLQAQFLLYHPQPLGLPMALLICLLKVIG YYIFRGANSQKNTFRKNPSDPSVAGLETIPTATGRQLLVSGWWGMVRHPNYLGDLIMALA WSLPCGLSHLLPYFYVLYFTALLVHREARDEQQCLQKYGRAWQEYCKRVPYRIIPYVY SEQ ID NO: 122 genomic|Rattus norvegicus computational transcript prediction from genomic

1 atggcttctc gtgaggcctc ccaggcccca ctggaattcg gggggccgtt gggcgtcacg 61 gcgatgctga tcctgctgcc tgccaccatg ttccacctgc ttctggcggc ccgctcgggt 121 ccggcgcgcc tcctggccct accagcctat ctgcctgggc tggaggagct gtggagccca

181 cgggctctgc tgctgttgtt catctggctc ggcctgcagg tggcgctcta tttgctgcct

241 gcacgcaagg tggccgaggg gctggaactg aaggacaaga gtcgcctgcg ctaccctatt

301 aatggtttcc aggctctggt gctaacagcc ctgttggtgg ggctaggggt gtcagttggg

361 ctgcccctgg gggcactccc tggaatgctc ctgcccctgg cctttgcgac cactctcacc

421 agctttatct tcagcctcct tctctatgca aaggctttgg tagctcctgc ctcagccctg

481 gctcctgggg gaaactcagg aaattctgtg tatgacttct ttctcggacg ggagctgaac

541 cctcgcctcg gttcctttga cttcaaatat ttctgtgagc tgcgacctgg cctcatcggc

601 tgggtcttca ttaacctggc cctgctgatg caggaggcgg agcttcgggg gagtccttca

661 ctggctatgt ggctggtcaa tggcttccag ttgctgtatg tgggtgatgc cctctggtat

721 gaggagtctg ttctcaccac catggacata atacatgatg gttttggctt catgctggtc

781 tttggagacc tggcctgggt accattcacc tacagcctgc aggcccagtt cctgttgtac

841 catccacagc ctctgggatt gcccatggcc ttgctcatct gcctcattaa ggctgttggt

901 tactacatct tccgaggggc caattcccag aaaaatacat tcagaaagaa tccttctgac

961 cccagtgtgg ctggtcttga gaccatccct actgccacgg ggaggcagct gttggtgtct

1021 gggtggtggg gtatggttcg acaccccaac tacctgggag acctcatcat ggctctggct

1081 tggtccttgc cctgtgggct gtcccacctg ctgccctact tctacctgct ctacttcact

1141 gcactgctgg tgcaccgcga ggcccgagat gagcagcagt gcctgcgaaa gtatggccgt

1201 gcctggcagg aatactgcaa gcgcgtgcct taccgaatca taccgtatgt ctactga

SEQIDNO: 123

AminoacidsequenceofratTM7SF2encodedbytheDNAsequenceshowninSEQIDNO: 122.

MASREASQAPLEFGGPLGVTAMLILLPATMFHLLLAARSGPARLLALPAYLPGLEELWSP RALLLLFIWLGLQVALYLLPARKVAEGLELKDKSRLRYPINGFQALVLTALLVGLGVSVG

LPLGALPGMLLPLAFATTLTSFIFSLLLYAKALVAPASALAPGGNSGNSVYDFFLGRELN

PRLGSFDFKYFCELRPGLIGWVFINLALLMQEAELRGSPSLAMWLVNGFQLLYVGDALWY

EESVLTTMDIIHDGFGFMLVFGDLAWVPFTYSLQAQFLLYHPQPLGLPMALLICLIKAVG

YYIFRGANSQKNTFRKNPSDPSVAGLETIPTATGRQLLVSGWWGMVRHPNYLGDLIMALA WSLPCGLSHLLPYFYLLYFTALLVHREARDEQQCLRKYGRAWQEYCKRVPYRIIPYVY

SEQIDNO: 124 gi|l 1545882|ref]NM_022144.1| Homo sapiens tenomodulin protein (TNMD), mRNA i tatctatgta acaaatcgca gcacaggagt cccctgggct ccctcaggct ctggtatgac

61 atatttgagc catataaatt cagcttctcc tctggcatct gttagccgac tcacttgcaa

121 ctccacctca gcagtggtct ctcagtcctc tcaaagcaag gaaagagtac tgtgtgctga

181 gagaccatgg caaagaatcc tccagagaat tgtgaagact gtcacattct aaatgcagaa

241 gcttttaaat ccaagaaaat atgtaaatca cttaagattt gtggactggt gtttggtatc

301 ctgaccctaa ctctaattgt cctgttttgg gggagcaagc acttctggcc ggaggtaccc

361 aaaaaagcct atgacatgga gcacactttc tacagcagtg gagagaagaa gaagatttac

421 atggaaattg atcctgtgac cagaactgaa atattcagaa gcggaaatgg cactgatgaa

481 acattggaag tacacgactt taaaaacgga tacactggca tctacttcgt gggtcttcaa

541 aaatgtttta tcaaaactca gattaaagtg attcctgaat tttctgaacc agaagaggaa

601 atagatgaga atgaagaaat taccacaact ttctttgaac agtcagtgat ttgggtccca

661 gcagaaaagc ctattgaaaa ccgagatttt cttaaaaatt ccaaaattct ggagatttgt

721 gataacgtga ccatgtattg gatcaatccc actctaatat cagtttctga gttacaagac

781 tttgaggagg agggagaaga tcttcacttt cctgccaacg aaaaaaaagg gattgaacaa

841 aatgaacagt gggtggtccc tcaagtgaaa gtagagaaga cccgtcacgc cagacaagca

901 agtgaggaag aacttccaat aaatgactat actgaaaatg gaatagaatt tgatcccatg

961 ctggatgaga gaggttattg ttgtatttac tgccgtcgag gcaaccgcta ttgccgccgc

1021 gtctgtgaac ctttactagg ctactaccca tatccatact gctaccaagg aggacgagtc

1081 atctgtcgtg tcatcatgcc ttgtaactgg tgggtggccc gcatgctggg gagggtctaa

1141 taggaggttt gagctcaaat gcttaaactg ctggcaacat ataataaatg catgctattc

1201 aatgaatttc tgcctatgag gcatctggcc cctggtagcc agctctccag aattacttgt 1261 aggtaattcc tctcttcatg ttctaataaa cttctacatt atcaaaaaa SEQ ID NO: 125

Amino acid sequence of human TNMD encoded by the DNA sequence shown in SEQ ID NO: 124. MAKNPPENCEDCHILNAEAFKSKKICKSLKICGLVFGILTLTLIVLFWGSKHFWPEVPKK AYDMEHTFYSSGEKKKIYMEIDPVTRTEIFRSGNGTDETLEVHDFKNGYTGIYFVGLQKC FIKTQIKVIPEFSEPEEEIDENEEITTTFFEQSVIWVPAEKPIENRDFLKNSKILEICDN VTMYWINPTLISVSELQDFEEEGEDLHFPANEKKGIEQNEQWVVPQVKVEKTRHARQASE EELPINDYTENGIEFDPMLDERGYCCIYCRRGNRYCRRVCEPLLGYYPYPYCYQGGRVIC RVIMPCNWWVARMLGRV

SEQ ID NO: 126 gi|31981227|ref|NM_022322.2| Mus musculus tenomodulin (Tnmd), niRNA i catatatggg tatatctatg taacaaatcg tagcacggga gccccctggg ctccctccgg

61 ctctggtatg acatatttga gccatataaa ttcagcttct cctccggcat ctggtagccg

121 actcacttgc aactccacct cagcagtagt cctctcagtc ctctcaaagc agggaaagag

181 caccgtgtgc tgggagacca tggcaaagaa tcctccagag aactgtgagg gctgtcacat

241 tctaaatgca gaagctctga aatctaagaa gatatgtaaa tcactgaaga tttgtggact

301 agtgtttggt atcctggcct taactctaat tgtcctgttt tgggggagca aacacttctg

361 gcccgaggta tccaagaaaa cctatgacat ggagcacact ttctacagca acggcgagaa

421 gaagaagatt tacatggaaa ttgatcccat aaccagaaca gaaatattca gaagtggaaa

481 tggcactgat gaaacattgg aagtccatga ctttaaaaat ggatacactg gcatctactt

541 tgtaggtctt caaaaatgct ttattaaaac tcaaatcaaa gtgattcctg aattttctga

601 accagaggaa gaaatagatg agaatgaaga aattactaca actttctttg aacagtcagt

661 gatttgggtt cccgcagaaa agcctattga aaacagagac ttcctgaaaa attctaaaat

721 tctggagatt tgcgataatg tgaccatgta ctggatcaat cccactctaa tagcagtttc

781 agaattacag gactttgagg aggacggtga agatcttcac tttcctacca gtgaaaaaaa

841 ggggattgac cagaatgagc aatgggtggt cccgcaagtg aaggtggaga agacccgcca

901 caccagacaa gcaagcgagg aagaccttcc tataaatgac tatactgaaa atggaattga

961 atttgaccca atgctggatg agagaggtta ctgttgtatt tactgtcgtc gaggcaaccg

1021 ttactgccgc cgtgtctgtg aacctttact aggctactac ccatacccct actgctacca

1081 aggaggtcga gtcatctgtc gtgtcatcat gccttgcaac tggtgggtgg cccgcatgct

1141 tgggagagtc taataggaag attgagttca aacgcttaac cttctgttag ccaatatata

1201 attaatgcat gctactccat gaatttctgc ctatgaggca tttgcctcca agtagcctat

1261 ccttcagaat tacttgtagg atattcctct cttcatgttc taataaactt ctacatcatc

1321 atcaaaaaaa aaaaaaaa

SEQIDNO: 127

Amino acid sequence of mouse TNMD encoded by the DNA sequence shown in SEQ ID NO: 126.

MAKNPPENCEGCHILNAEALKSKKICKSLKICGLVFGILALTLIVLFWGSKHFWPEVSKK TYDMEHTFYSNGEKKKIYMEIDPITRTEIFRSGNGTDETLEVHDFKNGYTGIYFVGLQKC FIKTQIKVIPEFSEPEEEIDENEEITTTFFEQSVIWVPAEKPIENRDFLKNSKILEICDN VTMYWINPTLIAVSELQDFEEDGEDLHFPTSEKKGIDQNEQWVVPQVKVEKTRHTRQASE EDLPINDYTENGIEFDPMLDERGYCCIYCRRGNRYCRRVCEPLLGYYPYPYCYQGGRVIC RVIMPCNWWVARMLGRV SEQIDNO: 128 gi|l 1560122|reflNM_022290.1| Rattus norvegicus tenomodulin (Tnmd), mRNA i tgtgcacaga agttatatac atatatgggt atatctatgt aacaaatcgt agcacgggag

61 ccccctgggc tccctccggc tctggtatga catatttgag ccatataaat tcagcttctc

121 ctctggcatc tgttagccga ctcacttgca actccacctc agcagtggtc tctcagtcct

181 ctcaaagcaa ggaaagagca ctgtgtgctg ggagaccatg gcaaagaatc ctccagagaa

241 ctgtgagggc tgtcacattc taaatgcaga agctctgaaa tctaagaaga tacgtaaatc

301 actgaagatt tgtggactag tgtttggtat cctggcctta actctaattg tcctgttttg

361 ggggagcaaa cacttctggc ccgaggtatc caagaagacc tatggcatgg agcacacttt

421 ctacagcaat ggcgagaaga agaagatttc catggaaatt gatcccataa ccagaacaga

481 aatattcaga agtggaaatg gcaccgatga aacattggaa gtccatgact ttaaaaacgg

541 atacactggc atctactttg taggtcttca aaaatgcttt attaaaactc aaatcaaagt

601 gattcctgaa ttttctgaac cagaagagga aatagatgag aatgaagaaa ttactacaac

661 gttctttgaa cagtcagtga tttgggttcc tgcagaaaag cctattgaaa acagagactt

721 cctgaaaaat tctaaaattc tggagatttg cgacaatgtg actatgtact ggatcaatcc

781 cactctaata gcagtttcag aattacagga ctttgaggag gatggtgaag atcttcactt

841 tcctaccagc gaaaaaaaag ggattgacca gaatgagcaa tgggtggtcc cacaagtgaa

901 ggtggagaag acccgccgca ccagacaagc aagcgaggaa gaccttcctg ttaatgacta

961 tactgaaaat ggaatcgaat ttgatcccat gctggatgag agaggttact gttgtattta

1021 ctgccgtcga ggcaaccgct actgccgcag ggtctgtgaa cctttactag gctactaccc

1081 atacccctac tgctaccaag gaggtcgagt catctgtcgt gtcatcatgc cttgcaactg

1141 gtgggtggcc cgcatgcttg ggagagtcta ataggaagtt tgagtccaaa tgcttaacct

1201 tttgttagcc aacatataat taatgcatgc tactccatga atttctgcat ttgcctccaa

1261 gtagcctatc ctccagaatt atttgtagga tattcctctc ttcgtgttct aataaacgtc

1321 tacatcatca tcaaaa SEQIDNO: 129

Amino acid sequence of rat TNMD encoded by the DNA sequence shown in SEQ ID NO: 128.

MAKNPPENCEGCHILNAEALKSKKIRKSLKICGLVFGILALTLIVLFWGSKHFWPEVSKK TYGMEHTFYSNGEKKKISMEIDPITRTEIFRSGNGTDETLEVHDFKNGYTGIYFVGLQKC FIKTQIKVIPEFSEPEEEIDENEEITTTFFEQSVIWVPAEKPIENRDFLKNSKILEICDN VTMYWINPTLIAVSELQDFEEDGEDLHFPTSEKKGIDQNEQWVVPQVKVEKTRRTRQASE EDLPVNDYTENGIEFDPMLDERGYCCIYCRRGNRYCRRVCEPLLGYYPYPYCYQGGRVIC RVIMPCNWWVARMLGRV

Claims

WHAT IS CLAIMED IS:

1. A method for identifying an agent for treating an obese, diabetic or pre-diabetic individual, the method comprising the steps of: (i) contacting an agent to a polypeptide encoded by a polynucleotide that hybridizes to a nucleic acid encoding cell and the cell is contacted with the agent. In some embodiments, the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129 in 50% formamide, 5X SSC, and 1% SDS at 42⁰C followed by a wash in 0.2X SSC, and 0.1 % SDS at 55⁰C; and (ii) selecting an agent that modulates the expression or activity of the polypeptide or that binds to the polypeptide, thereby identifying an agent for treating an obese, diabetic or pre-diabetic individual.

2. The method of claim 1, wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129 or a protein domain thereof.

3. The method of claim 1 , the method further comprising detecting whether the selected agent modulates weight and/or obesity.

4. The method of claim 1 , the method further comprising detecting whether the selected agent modulates insulin sensitivity.

5. The method of claim 1, wherein step (ii) comprises selecting an agent that modulates expression of the polypeptide.

6. The method of claim 1, wherein step (ii) comprises selecting an agent that modulates the activity of the polypeptide.

7. The method of claim 1, wherein step (ii) comprises selecting an agent that specifically binds to the polypeptide.

8. The method of claim 1 , wherein the polypeptide is expressed in a cell and the cell is contacted with the agent.

9. The method of claim 1 , wherein the polypeptide comprises SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127 or 129