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  • Review Article
  • Published:

Monogenic causes of X-linked mental retardation

Nature Reviews Genetics volume 2, pages 669–680 (2001)Cite this article

Key Points

  • Mental retardation, as reflected by impaired cognitive function, is the most common cause of handicap in children and young adults. Its underlying causes are heterogeneous, and include genetic and environmental factors.

  • Many disease genes associated with mental retardation have been identified in recent years. Impaired cognitive function is seen in monogenic metabolic and developmental disorders, and as a result of chromosomal rearrangements.

  • Mental retardation has a 20–30% higher incidence in males than in females, indicating that some forms of the disorder are X linked. Work on syndromic and nonspecific forms of X-linked mental retardation (XLMR) are beginning to identify causative mutations in X-linked genes.

  • Disease genes have recently been identified in three syndromic forms of XLMR: ATRX, Coffin–Lowry and Rett syndromes. The genes affected in these diseases are all believed to be involved in chromatin remodelling, providing an important insight into a cellular process that might be perturbed in individuals with mental retardation.

  • Nonspecific forms of XLMR are a greater challenge to study owing to their clinical and genetic heterogeneity, but recent progress in this area has been made. Mutations have been found in several genes that act in signal transduction pathways in neuronal cells in patients with nonspecific XLMR. Some of these mutations are likely to alter cytoskeletal dynamics and neuronal morphogenesis. Genes that are involved in syndromic XLMR have also been found to be mutated in nonspecific forms of the disorder.

  • The pooling of clinical and genetic resources, and new sequence data, are likely to lead to further discoveries of genes involved in mental retardation, both on the X chromosome and autosomes. How these findings can be applied diagnostically, however, remains an open question, given the difficulty of screening some of the larger genes involved in mental retardation and the clinical heterogeneity of some of the disorders.

Abstract

Mutations in X-linked genes are likely to account for the observation that more males than females are affected by mental retardation. Causative mutations have recently been identified in both syndromic X-linked mental retardation (XLMR) and in the genetically heterogeneous 'nonspecific' forms of XLMR, for which cognitive impairment is the only defining clinical feature. Proteins that function in chromatin remodelling are affected in three important syndromic forms of XLMR. In nonspecific forms of the disorder, defects have been found in signal-transduction pathways that are believed to function during neuronal maturation. These findings provide important insights into the molecular and cellular defects that underlie mental retardation.

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Figure 1: Genes and loci involved in nonspecific X-linked mental retardation.
Figure 2: Expansion mutations at FMR1 and FMR2.
Figure 3: Signal transduction pathways and X-linked mental retardation.

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Acknowledgements

Research on XLMR in the authors' labs is supported by INSERM, EEC and Fondation pour la Recherche Médicale (J.C. and J.L.M.), by funds from Association Française syndrome de Rett, AFM and Fondation Jerome Lejeune (to J.C.), and by FRAXA foundation, CNRS and the Hôpital Universitaire de Strasbourg (HUS) (to J.L.M.).

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Authors and Affiliations

  1. Institut Cochin de Génétique Moléculaire, CNRS/INSERM, CHU Cochin, 75014, Paris, France

    Jamel Chelly

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, Illkirch, CU Strasbourg, France

    Jean-Louis Mandel

Authors
  1. Jamel Chelly
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  2. Jean-Louis Mandel
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DATABASE LINKS

Smith–Lemli–Opitz

Duchenne muscular dystrophy

Prader–Willi

Angelman

Williams–Beuren

fragile X

FMR1

Lesch–Nyhan

adrenoleukodystrophy

mucopolysaccharidosis type II

Menkes

Pelizaeus–Merzbacher

ATRX

Coffin–Lowry

Rett

MECP2

ATRX

Juberg–Marsidi

Smith–Fineman–Myers

Enhancer of zeste

RSK2

RSK4

ERK kinase

FOS

EGF

CBP co-activator

Rubinstein–Taybi

FMR2

GDI1

RAB3A

Gdi1

Rab3a

OPHN1

PAK3

ARHGEF6

RhoA

Cdc42

TM4SF2

late bloomer

Scab

MAOA

MAOB

Fmr1

FURTHER INFORMATION

Wechsler intelligence scale

Stanford Binet intelligence scale

XLMR Genes Update web site

Jean-Louis Mandel's lab

Glossary

PHENYLKETONURIA

An inborn error of metabolism caused by lack of the enzyme that converts phenylalanine to tyrosine. It causes abnormally high phenylalanine levels and severe, progressive mental retardation if untreated, but can be prevented by neonatal screening and a low phenylalanine diet from an early age.

HOLOPROSENCEPHALY

A failure of the forebrain (prosencephalon) to divide into hemispheres or lobes, often accompanied by a deficit in midline facial development.

FRAGILE SITE

Chromosomal anomaly that appears as a region of decondensed or partially broken mitotic chromosomes under specific karyotyping conditions. The FRAXA and FRAXE fragile sites contain expanded CGG repeats that are methylated, affecting the expression of the FMR1 and FMR2 genes, respectively.

HYDROCEPHALUS

A condition, marked by the expansion of cerebral ventricles and by the compression of neural structures, that is caused by a block in the flow of cerebral spinal fluid or its overproduction.

LISSENCEPHALY

A brain malformation characterized by the incomplete development of the folds (gyri) of the outer region of the brain (the cerebral cortex), which causes the surface of the brain to appear abnormally thickened and unusually smooth.

THALASSAEMIA

Inherited disorders that are caused by the defective production of either the α- or β-globin chains of haemoglobin.

SNF/SWI

Chromatin-remodelling multiprotein complex initially identified genetically in yeast. Related complexes exist in mammals and are involved in the activation and repression of various genes.

SYNDROME LUMPING

When syndromes described under different names and with different clinical features are found to be caused by mutations in the same gene. Syndrome splitting is also common, when a clinical diagnosis that was thought to correspond to a single disease is shown to be caused by mutations in different genes.

HETEROCHROMATIN

Late-replicating, gene-sparse, condensed chromatin regions that are rich in repeated sequence.

ACROCENTRIC

When a centromere is close to one end of a chromosome.

HETEROCHROMATIN PROTEIN 1

(HP1). A protein that binds to highly repetitive, heterochromatic satellite DNA at centromeres and telomeres.

ENCEPHALOPATHY

A degenerative condition of the brain that can be caused by infectious disease, metabolic abnormalities, brain tumours, toxic drug effects or increased intercranial pressure.

PREMUTATION

An unstable mutation that has no phenotypic effect but that is highly likely to mutate to a full mutation during transmission through the germ line, as is seen with some expanding trinucleotide repeats.

PYRAMIDAL NEURON

A class of neuron in the cerebral cortex with a pyramid-shaped cell body. These neurons send long axons down the spinal cord and form dendrites that extend laterally through the cortical layer that contains the cell body.

GROWTH CONE

The motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

FILOPODIA

Long, thin finger-like exploratory cell extensions found in crawling cells and growth cones.

LAMELLIPODIA

Thin, sheet-like cell extensions found at the leading edge of crawling cells or growth cones.

INTEGRINS

Transmembrane proteins that function as heterodimers and are involved in cell–cell and cell–extracellular-matrix interactions.

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Chelly, J., Mandel, JL. Monogenic causes of X-linked mental retardation. Nat Rev Genet 2, 669–680 (2001). https://doi.org/10.1038/35088558

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