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Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency

Nature Genetics volume 34, pages 434–439 (2003)Cite this article

Abstract

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability3. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11β-HSD1 catalyzes the reduction of cortisone to cortisol4 whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone5. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase4,5. But the catalytic domain of 11β-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER7, thereby influencing directionality of 11β-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11β-HSD1 expression and ER NADPH generation with loss of 11β-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

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Figure 1: Sequence analysis of HSD11B1.
Figure 2: Functional analyses of HSD11B1 intron 3 mutation.
Figure 3: Switch in 11β-HSD1 activity concomitant with increase in H6PDH.
Figure 4: Sequence analysis of H6PD.
Figure 5: H6PDH activity assays on stably transfected WRL68 cells.

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Acknowledgements

The authors thank J. Ride for advice and discussions developing the hypothesis that 11β-HSD1 is critically dependent on cofactor regeneration. This work was supported by grants from the Medical Research Council (Senior Clinical Fellowship to P.M.S. and Clinical Training Fellowship to J.W.T.) and The Wellcome Trust. Part of the research was undertaken in the Wellcome Clinical Research Facility. W.A. is a Heisenberg Senior Clinical Fellow of the Deutsche Forschungsgemeinschaft.

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Author notes

  1. Nicole Draper and Elizabeth A Walker: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, B15 2TH, Birmingham, UK

    Nicole Draper, Elizabeth A Walker, Iwona J Bujalska, Jeremy W Tomlinson, Susan M Chalder, Wiebke Arlt, Gareth G Lavery, Oliver Bedendo, Martin Hewison & Paul M Stewart

  2. Endocrine Sciences Research Group, University of Manchester, Manchester, UK

    David W Ray

  3. Department of Clinical Biochemistry, Manchester Royal Infirmary, Manchester, M13 9WL, UK

    Ian Laing

  4. Department of Laboratory Diagnostics, The Children's Memorial Health Institute, Warsaw, Poland

    Ewa Malunowicz

  5. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Perrin C White

  6. Department of Haematology, Hammersmith Hospital, Imperial College School of Medicine, London, UK

    Philip J Mason

  7. MRC Blood Pressure Unit, University of Glasgow, Glasgow, UK

    John M Connell

  8. Steroid Laboratory, Childrens' Hospital Medical Center, Oakland, California, USA

    Cedric H L Shackleton

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Correspondence to Paul M Stewart.

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Draper, N., Walker, E., Bujalska, I. et al. Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet 34, 434–439 (2003). https://doi.org/10.1038/ng1214

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