In a 46,XY male with ambiguous external genitalia and combined partial 17-alpha-hydroxylase/17,20-lyase deficiency (202110), Ahlgren et al. (1992) identified compound heterozygosity for mutations in the CYP17A1 gene: a C-to-T transition in exon 4, resulting in an arg239-to-ter (R239X) substitution, and a C-to-A transversion in exon 6, resulting in a pro342-to-thr substitution (P342T; 609300.0007). The mutations were inherited from the mother and father, respectively. The R239X mutation occurred at the N-terminal side of the heme-binding sequence and the putative resultant truncated protein was nonfunctional. Reconstruction of the P342T mutation by site-directed mutagenesis into human CYP17 cDNA followed by expression in COS-1 cells led to a normal amount of immunodetectable P450-17-alpha protein, although both the hydroxylase and the lyase activities were reduced to 40 to 45% of normal. The presence of ambiguous external genitalia indicated that greater than 20% of the normal 17,20-lyase activity is required for complete virilization in the male.
In 3 sisters with breast cancer (114480) diagnosed at ages 34, 38, and 42 years, respectively, Hopper et al. (2005) identified a germline R239X mutation in the CYP17A1 gene. None of the 3 sisters carried a deleterious mutation in BRCA1 (113705) or BRCA2 (600185). A sister who was cancer-free at age 58 did not have the R239X mutation; the mutation was not found in 788 controls.
