HSD11B1 – Cortisone Reductase Deficiency

HSD11B1 encodes the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, which catalyzes the reduction of cortisone to cortisol at a prereceptor level. Loss of this activity leads to cortisone reductase deficiency (Cortisone Reductase Deficiency), characterized by increased cortisol clearance, ACTH-mediated hyperandrogenism and a PCOS-like phenotype.

Genetic evidence supports an autosomal recessive/digenic model in three unrelated patients carrying intronic HSD11B1 variants that reduce transcription alongside H6PD mutations (PMID:12858176). In addition, two unrelated cases with normal H6PD sequences harbor novel heterozygous missense variants—c.561G>T (p.Lys187Asn) and c.409C>T (p.Arg137Cys)—consistent with an autosomal dominant, dominant-negative mechanism (PMID:21325058). Segregation data are limited.

The variant spectrum includes noncoding intronic changes impairing mRNA levels and missense substitutions at conserved residues within the catalytic domain. The c.561G>T (p.Lys187Asn) substitution abolishes reductase activity and disrupts dimer assembly, while intronic alleles decrease HSD11B1 transcript abundance.

Functional assays in bacterial and mammalian systems show complete loss or severe reduction of 11β-HSD1 oxo-reductase activity for coding variants and diminished mRNA expression for intronic alleles, concordant with patient steroid profiles (PMID:12858176, PMID:21325058). Rescue experiments are not reported.

No studies have refuted the association; CRD-related HSD11B1 variants are not observed in large PCOS cohorts without steroid abnormalities, and H6PD-only variants lack CRD profiles. Additional heterozygous or triallelic models may exist but exceed current evidence.

Overall, moderate genetic validity supported by strong functional data establishes HSD11B1 as a CRD gene. Testing for HSD11B1 variants in patients with hyperandrogenism and atypical steroid metabolite ratios enables precise diagnosis and tailored 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
• Proceedings of the National Academy of Sciences of the United States of America | 2011 | Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1. PMID:21325058

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