Endocrine Abstracts

In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyses the reduction of cortisone to cortisol within the endoplasmic reticulum. For functional 11-ketoreductase activity, 11β-HSD1 requires the NADPH-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH). Loss of 11-ketoreductase activity results in increased cortisol clearance and activation of the HPA axis with hyperandrogenism. To date only mutations in H6PDH have been identified as the cause of disease in such cases – a condition termed apparent cortisone reductase deficiency (ACRD).

We examined the HSD11B1 gene in two cases presenting with hyperandrogenism and premature pseudopuberty with biochemical features indicative of a milder form of ACRD in whom the H6PD gene was normal. Both cases were heterozygous for mutations (R137C or K187N) in HSD11B1. Modelling the R137C mutation indicated potential disruption of a salt bridge at the dimer interface of the 11β-HSD1 protein, whilst the K187N mutation was predicted to affect cofactor binding. Following expression of the mutants in mammalian cells, only 5% of wild-type (WT) activity was detected for R137C, and no activity for the K187N mutant. Expression in Escherichia coli also demonstrated greatly reduced (R137C), or undetectable (K187N), activity. We then developed a novel bacterial ‘hybrid dimer’ system to examine the effects of simultaneous expression of mutant and WT 11β-HSD1. Analysis of the resulting mutant-WT heterodimers revealed that, for both R137C and K187N, mutations to one monomer of the 11β-HSD1 dimer were able to decrease the yield of soluble protein, presumably by affecting protein folding. This study has identified novel heterozygous mutations in the HSD11B1 gene and has shown that mutations in one monomer of this dimeric protein can have a dominant negative effect on the WT partner. True ‘cortisone reductase deficiency’ due to mutations in HSD11B1 is a further monogenic cause of hyperandrogenism/premature pseudopuberty.