| Title: |
Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency |
| Authors: |
Draper, Nicole; Walker, Elizabeth A.; Bujalska, Iwona J.; Tomlinson, Jeremy W.; Chalder, Susan M.; Arlt, Wiebke; Lavery, Gareth G.; Bedendo, Oliver; Ray, David W.; Laing, Ian; Malunowicz, Ewa; White, Perrin C.; Hewison, Martin; Mason, Philip J.; Connell, John M.; Shackleton, Cedric H L; Stewart, Paul M. |
| Source: |
Draper, N, Walker, E A, Bujalska, I J, Tomlinson, J W, Chalder, S M, Arlt, W, Lavery, G G, Bedendo, O, Ray, D W, Laing, I, Malunowicz, E, White, P C, Hewison, M, Mason, P J, Connell, J M, Shackleton, C H L & Stewart, P M 2003, 'Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency', Nature Genetics, vol. 34, no. 4, pp. 434-439. https://doi.org/10.1038/ng1214 |
| Publication Year: |
2003 |
| Collection: |
The University of Manchester: Research Explorer - Publications |
| Subject Terms: |
11-beta-Hydroxysteroid Dehydrogenase Type 2; Amino Acid Sequence; Base Sequence; genetics: Carbohydrate Dehydrogenases; Case-Control Studies; Cell Line; deficiency: Cortisone Reductase; genetics: DNA; Complementary; metabolism: Endoplasmic Reticulum; Exons; Female; Humans; genetics: Hydroxysteroid Dehydrogenases; Male; Molecular Sequence Data; Mutation; metabolism: NADP; Oxidation-Reduction; Phenotype; etiology: Polycystic Ovary Syndrome; genetics: RNA; Messenger; Sequence Homology; Amino Acid; Transfection |
| Description: |
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 bioavailability. 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 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 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 ER, 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 oxoreductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1061-4036; 1546-1718 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pissn/1061-4036; info:eu-repo/semantics/altIdentifier/eissn/1546-1718 |
| DOI: |
10.1038/ng1214 |
| Availability: |
https://research.manchester.ac.uk/en/publications/2622633d-d93c-41d0-895d-e30a4a4157e9; https://doi.org/10.1038/ng1214 |
| Rights: |
info:eu-repo/semantics/closedAccess |
| Accession Number: |
edsbas.7196CA8F |
| Database: |
BASE |