Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency

Nat Genet. 2003 Aug;34(4):434-9. doi: 10.1038/ng1214.


In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Amino Acid Sequence
  • Base Sequence
  • Carbohydrate Dehydrogenases / genetics*
  • Carbohydrate Dehydrogenases / metabolism
  • Case-Control Studies
  • Cell Line
  • Cortisone Reductase / deficiency*
  • DNA, Complementary / genetics
  • Endoplasmic Reticulum / metabolism
  • Exons
  • Female
  • Humans
  • Hydroxysteroid Dehydrogenases / genetics*
  • Hydroxysteroid Dehydrogenases / metabolism
  • Male
  • Molecular Sequence Data
  • Mutation*
  • NADP / metabolism
  • Oxidation-Reduction
  • Phenotype
  • Polycystic Ovary Syndrome / etiology
  • Polycystic Ovary Syndrome / genetics
  • Polycystic Ovary Syndrome / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Homology, Amino Acid
  • Transfection


  • DNA, Complementary
  • RNA, Messenger
  • NADP
  • Carbohydrate Dehydrogenases
  • Hydroxysteroid Dehydrogenases
  • galactose-6-phosphate dehydrogenase
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • HSD11B2 protein, human
  • Cortisone Reductase

Associated data

  • GENBANK/AL022398
  • GENBANK/AL031316
  • GENBANK/Z98044