A new insight into the molecular basis of 3 beta-hydroxysteroid dehydrogenase deficiency

Classical 3 beta -hydroxysteroid dehydrogenase/Delta (5)-Delta (4) isomeras e (3 beta -HSD) deficiency is a rare form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads resulting fro m mutations in the HSD3B2 gene, causing varying degrees of salt-loss in bot h sexes and incomplete masculinization of the external genitalia in genetic males. To date a total of 34 mutations (including 5 frameshift, 4 nonsense , I in-frame deletion, I splicing and 23 missense mutations) have been iden tified in the HSD3B2 gene. Results from functional charaterization studies of the mutant proteins agrees with the prediction that no functional type I I 3 beta -HSD isoenzyme is expressed in the adrenals and gonads of the pati ents with the severe salt-losing form, whereas the nonsalt-losing form caus es an incomplete loss in enzymatic activity, thereby leaving sufficient enz ymatic activity to prevent salt loss. Recent studies have highlighted the f act that various mutations appear to have a drastic effect upon the stabili ty of the protein, therefore providing molecular evidence of a new mechanis m involved in classical 3 beta -HSD deficiency. Finally, the functional cha racterization of the missense mutations known to be involved in this autoso mal recessive disorder provides valuable information concerning the structu re-function relationships of the 3 beta- HSD enzyme superfamily.