Phenotypic variability and origins of mutations in the gene encoding 3 beta-hydroxysteroid dehydrogenase type II

Mutations in HSD3B2, the gene for 3 beta-hydroxysteroid dehydrogenase type II (3 beta-HSD II) hale been detected and activities analysed through the i n vitro expression of mutant cDNAs. Two full sibs with male pseudohermaphro ditism were found to be double heterozygotes: N100S/266 Delta A. This genot ype leads to the most profound loss of 3 beta-HSD II enzyme activity (1.3% of normal) described to date in cases without severe salt-loss. One sib (N1 00S/266 Delta A) is the first reported male case of type II deficiency affe cted with premature adrenarche. Three apparently independent kindreds had p ropositi affected with the HSD3B2 mutation A82T/A82T, which is associated w ith a non-salt-losing phenotype with variable expressivity in females. Thes e three families had the same extended HSD3B haplotype and are likely to ha ve inherited the same ancestral mutation. The significance of this finding is discussed in the light of the presence of A82T mutation at a homologous position in pseudogene phi 5 that is present in the HSD3B cluster.