H6PD – Cortisone Reductase Deficiency 1

Hexose-6-phosphate dehydrogenase (H6PD) generates NADPH in the endoplasmic reticulum to support 11β-hydroxysteroid dehydrogenase type 1 oxo-reductase activity, converting cortisone to cortisol. Biallelic loss of H6PD function defines cortisone reductase deficiency 1 (CRD1), an autosomal recessive disorder presenting with HPA axis activation and androgen excess.

Multiple unrelated probands (n = 9) with compound heterozygous or homozygous H6PD variants were reported: the recurrent missense allele c.1358G>A (p.Arg453Gln) occurred alone or with frameshift and nonsense changes ([PMID:12858176]; [PMID:18628520]; [PMID:23132696]).

The variant spectrum includes missense (p.Arg453Gln), nonsense (p.Tyr316Ter), frameshift (p.Arg109fs, p.Glu621ThrfsTer4) and splice‐site alleles. The c.1358G>A (p.Arg453Gln) variant is observed recurrently in CRD1 cohorts.

Functional assays demonstrate that both missense and truncating H6PD alleles abolish enzyme activity, impair ER NADPH regeneration and abrogate 11β-HSD1 oxo-reductase function, consistent with human endocrine phenotypes ([PMID:12858176]; [PMID:18628520]).

Common polymorphisms, including R453Q, occur at appreciable frequency in the general population (7% triallelic genotype in 3551 subjects) without altering cortisol/cortisone ratios or PCOS risk ([PMID:16091483]; [PMID:15827106]).

Integration of genetic and experimental data supports a strong autosomal recessive gene–disease relationship. Urinary steroid profiling reliably distinguishes CRD1 from PCOS, and targeted H6PD sequencing enables definitive diagnosis and personalized management. Key take-home: H6PD mutation analysis is essential for accurate diagnosis of cortisone reductase deficiency 1.

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
• European Journal of Endocrinology • 2013 • Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling. PMID:23132696
• The Journal of Clinical Endocrinology and Metabolism • 2005 • Genotypes at 11beta-hydroxysteroid dehydrogenase type 11B1 and hexose-6-phosphate dehydrogenase loci are not risk factors for apparent cortisone reductase deficiency in a large population-based sample. PMID:16091483
• The Journal of Clinical Endocrinology and Metabolism • 2005 • A study of the hexose-6-phosphate dehydrogenase gene R453Q and 11beta-hydroxysteroid dehydrogenase type 1 gene 83557insA polymorphisms in the polycystic ovary syndrome. PMID:15827106

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