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

Draper N, Walker E, Bujalska I, Tomlinson J, Chalder S, Arlt W, Lavery G, Bedendo O, Ray DW, Laing I, Malunowicz E, White P, Hewison M, Mason P, Connell J, Shackleton C, Stewart PM

Nat Genet. 2003;34:434-439.

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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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-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 ER, thereby influencing directionality of 11beta-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 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-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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Publication type:
Publication form:
Published date:
Journal title:
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Place of publication:
United States
Volume:
34
Start page:
434
End page:
439
Digital Object Identifier:
10.1038/ng1214
Access state:
Active

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Record metadata

Manchester eScholar ID:
uk-ac-man-scw:1d20323
Created:
30th August, 2009, 15:39:27
Last modified by:
Ray, David
Last modified:
19th August, 2013, 18:14:56

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