ABSTRACT
Classical 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD) deficiency is a form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads resulting from mutations in the HSD3B2 gene and causing varying degrees of saltwasting in both sexes and incomplete masculinization of the external genitalia in genetic males. Although an elevated ratio of Δ5/Δ4-steroids was considered to be the best biological parameter for the diagnosis of this deficiency, the best criteria now appears to be plasma levels of 17-hydroxypregnenolone greater than l00nmol/L following stimulation with ACTH. To date, a total of 34 mutations (including five frameshift, four nonsense, one inframe deletion, one splicing and 23 missense mutations) have been identified in the HSD3B2 gene in 56 individuals from 44 families suffering from classical 3β-HSD deficiency. The functional results obtained with mutant proteins are in agreement with the prediction that no functional type II 3β-HSD isoenzyme is expressed in the adrenals and gonads of the patients suffering from a severe salt-wasting form, whereas the nonsalt-losing form, also resulting from missense mutation(s) in the HSD3B2 gene, causes an incomplete loss in enzymatic activity, thereby leaving sufficient enzymatic activity to prevent salt wasting. Moreover, recent studies have highlighted the fact that various mutations appear to have a drastic effect upon the stability of the protein, therefore providing molecular evidence of a new mechanism involved in classical 3β-HSD deficiency. However, the functional data available concerning the sequence variants, which were detected in individuals with premature pubarche or hyperandrogenic adolescent girls suspected to be affected by nonclassical 3β-HSD deficiency, coupled with the previous studies reporting that no mutations were found in both the HSD3B1 and/or HSD3B2 genes in such patients, strongly supports the conclusion that this disorder does not result from a mutant 3β-HSD isoenzyme. Finally, the functional characterization of missense mutations known to be involved in this autosomal recessive disorder associated with male pseudohermaphroditism also provides valuable information concerning the structure-function relationships of the 3β-HSD enzyme superfamily.
