Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency

Lavery, G. G. et al. (2008) Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. Journal of Clinical Endocrinology and Metabolism, 93(10), pp. 3827-3832. (doi:10.1210/jc.2008-0743)

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Publisher's URL: http://dx.doi.org/10.1210/jc.2008-0743

Abstract

Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11β-HSD1 oxoreductase activity requires the reduced nicotinamide adenine dinucleotide phosphate-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligo-amenorrhea, 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 11β-HSD1 (Intron 3 inserted adenine) interact to cause CRD.

Objective: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD.

Design: We analyzed 24-h urine collection for steroid biomarkers by gas chromatography/mass spectrometry and sequenced the HSD11B1 and H6PD genes in our CRD cohort.

Patients: Patients included four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD.

Results: Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G→A and D620fsX3) for mutations inH6PD. 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 11β-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11β-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stewart, Prof Paul and Connell, Professor John
Authors: Lavery, G. G., Walker, E. A., Tiganescu, A., Ride, J. P., Shackleton, C. H. L., Tomlinson, J. W., Connell, J. M. C., Ray, D. W., Biason-Lauber, A., Malunowicz, E. M., Arlt, W., and Stewart, P. M.
College/School:College of Medical Veterinary and Life Sciences
Journal Name:Journal of Clinical Endocrinology and Metabolism
Publisher:The Endocrine Society
ISSN:0021-972X
ISSN (Online):1945-7197
Published Online:02 July 2013
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences