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 |
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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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