Nature Genetics
34, 434 - 439 (2003)
Published online: 13 July 2003; | doi:10.1038/ng1214
Mutations in the genes encoding 11 -hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiencyNicole Draper1, 9, Elizabeth A Walker1, 9, Iwona J Bujalska1, Jeremy W Tomlinson1, Susan M Chalder1, Wiebke Arlt1, Gareth G Lavery1, Oliver Bedendo1, David W Ray2, Ian Laing3, Ewa Malunowicz4, Perrin C White5, Martin Hewison1, Philip J Mason6, John M Connell7, Cedric H L Shackleton8
& Paul M Stewart11
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. 2
Endocrine Sciences Research Group, University of Manchester, Manchester, UK. 3
Department of Clinical Biochemistry, Manchester Royal Infirmary, Manchester M13 9WL, UK. 4
Department of Laboratory Diagnostics, The Children's Memorial Health Institute, Warsaw, Poland. 5
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 6
Department of Haematology, Hammersmith Hospital, Imperial College School of Medicine, London, UK. 7
MRC Blood Pressure Unit, University of Glasgow, Glasgow, UK. 8
Steroid Laboratory, Childrens' Hospital Medical Center, Oakland, California, USA. 9
These authors contributed equally to this work.
Correspondence should be addressed to Paul M Stewart p.m.stewart@bham.ac.ukIn 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 11 -hydroxysteroid dehydrogenase type 1 (11-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, 11-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 11-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 11-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 11-HSD1 expression and ER NADPH generation with loss of 11-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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-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation
