Steroid Biomarkers and Genetic Studies Reveal Inactivating Mutations in Hexose-6-Phosphate Dehydrogenase in Patients with Cortisone Reductase Deficiency

Gareth Lavery, Elizabeth Walker, A Tiganescu, Jonathan Ride, Cedric Shackleton, Jeremy Tomlinson, JM Connell, DW Ray, A Biason-Lauber, EM Malunowicz, Wiebke Arlt, Paul Stewart

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Context. Cortisone Reductase Deficiency (CRD) is characterised by a failure to regenerate cortisol from cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11beta-HSD1 oxo-reductase activity requires the NADPH-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligoamenorrhoea, and infertility in females and premature pseudopuberty in males. Recent association studies have failed to corroborate findings that polymorphisms in the genes encoding H6PDH (R453Q) and 11beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD. Objective. Revaluate the genetics and steroid biochemistry of patients with CRD. Design. Analyse 24 h urine collection for steroid biomarkers by GC/MS and sequence the HSD11B1 and H6PD genes in our CRD cohort. Patients. Four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD. Results. GC/MS identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, G359D) and one case identified as compound heterozygous (c.960G>A and D620fsX3) for mutations in H6PD. No mutations affecting enzyme activity were identified in the HSD11B1 gene. Expression and activity assays demonstrate loss-of-function for all reported H6PDH mutations. Conclusions. CRD is caused by inactivating mutations in the H6PD gene, rendering the 11beta-HSD1 enzyme unable to operate as an oxo-reductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11beta-HSD1 - H6PDH pathway in regulating HPA axis activity.
Original languageEnglish
Pages (from-to)3827-3832
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number10
DOIs
Publication statusPublished - 15 Jul 2008

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