Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency
Author(s)
Type
Journal Article
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 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 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.
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 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 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.
Date Issued
2008-10-01
Date Acceptance
2008-07-03
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2008, 93 (10), pp.3827-3832
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
3827
End Page
3832
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
93
Issue
10
Copyright Statement
Copyright © 2008 by The Endocrine Society.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/18628520
PII: jc.2008-0743
Subjects
DIAGNOSIS
ENCODING 11-BETA-HYDROXYSTEROID DEHYDROGENASE
Endocrinology & Metabolism
HYPERCORTISOLISM
Life Sciences & Biomedicine
MASS-SPECTROMETRY
METABOLISM
MICE
OBESITY
POLYCYSTIC-OVARY-SYNDROME
Science & Technology
SELECTIVE-INHIBITION
TYPE-1
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2008-07-15