H6PD – Cortisone Reductase Deficiency

Cortisone reductase deficiency (CRD) is an autosomal recessive disorder characterized by failure to regenerate cortisol from cortisone in peripheral tissues, leading to compensatory ACTH‐driven adrenal androgen excess and features including hirsutism, oligo-amenorrhea, infertility, and premature pseudopuberty. The H6PD gene (hexose-6-phosphate dehydrogenase) encodes an endoplasmic reticulum enzyme that supplies NADPH to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), thus directing its oxo-reductase activity toward cortisol formation. Disruption of H6PD results in insufficient ER NADPH, loss of 11β-HSD1 reductase function, and the CRD phenotype ([PMID:12858176]).

Seven unrelated probands with CRD have been described harboring biallelic or triallelic H6PD variants across two cohorts, consistent with an autosomal recessive inheritance model and functional loss of enzyme activity ([PMID:12858176], [PMID:18628520]). Variant spectrum includes four protein-truncating alleles (p.Tyr316Ter, p.Arg109fs, p.Glu621ThrfsTer4, frameshift D620fsX3) and two missense changes (p.Gly359Asp, p.Arg453Gln). Recurrent mutations such as c.948C>G (p.Tyr316Ter) appear in multiple patients, supporting their pathogenicity.

The variant c.948C>G (p.Tyr316Ter) results in premature termination of H6PD and was identified in homozygosity in several CRD cases, abolishing NADPH generation and 11β-HSD1 oxo-reductase activity in patient‐derived samples ([PMID:12858176]).

Functional assays in vitro and ex vivo demonstrate that H6PDH mutants fail to generate sufficient NADPH within the ER lumen, eliminating 11β-HSD1-dependent cortisone reduction and recapitulating CRD biochemical hallmarks including elevated cortisone/cortisol ratios and ACTH-mediated androgen excess ([PMID:18628520]). Rescue of 11β-HSD1 activity only occurs upon exogenous NADPH supply, confirming a loss-of-function mechanism.

A case-control study in polycystic ovary syndrome (PCOS) cohorts found no association between CRD‐linked H6PD variants and PCOS susceptibility or adrenal steroid measures, indicating that these alleles specifically underlie rare CRD rather than common hyperandrogenic disorders ([PMID:16817821]).

In summary, robust genetic and experimental data across seven CRD probands support a Strong gene–disease association for H6PD and cortisone reductase deficiency. Loss-of-function H6PD mutations lead to ER NADPH deficit, impaired 11β-HSD1 reductase activity, and classic CRD clinical features. Genetic testing of H6PD should be integrated into the diagnostic workup of suspected CRD cases presenting with unexplained hyperandrogenism.

Key Take-home: H6PD inactivating mutations cause CRD via ER NADPH depletion and 11β-HSD1 oxo-reductase failure, warranting targeted genetic testing for accurate diagnosis and management.

References

• Nature Genetics • 2003 • Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. PMID:12858176
• The Journal of Clinical Endocrinology and Metabolism • 2008 • Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. PMID:18628520
• Clinical Endocrinology • 2006 • Variants implicated in cortisone reductase deficiency do not contribute to susceptibility to common forms of polycystic ovary syndrome. PMID:16817821

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