Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5 alpha dihydrotestosterone availability

Mutations in the androgen receptor (AR) gene result in a wide range of phen otypes of the androgen insensitivity syndrome (AIS). Inter- and intrafamili al differences in the phenotypic expression of identical AR mutations are k nown, suggesting modifying factors in establishing the phenotype. Two 46,XY siblings with partial AIS sharing the same AR gene mutation, R846 H, but showing very different phenotypes are studied. Their parents are fir st cousins. One sibling with grade 5 AIS was raised as a girl; the other si bling with grade 3 ALS was raised as a boy. In both siblings serum levels o f hormones were measured; a sex hormone-binding globulin (SHBG) suppression test was completed; and mutation analysis of the AR gene, Scatchard, and S DS-PAGE analysis of the AR protein was performed. Furthermore, 5 alpha -red uctase 2 expression and activity in genital skin fibroblasts were investiga ted, and the 5 alpha -reductase 2 gene was sequenced. The decrease in SHBG serum levels in a SHBG suppression test did not sugges t differences in androgen sensitivity as the cause of the phenotypic variat ion. Also, androgen binding characteristics of the AR, AR expression levels , and the phosphorylation pattern of the AR on hormone binding were identic al in both siblings. However, 5 alpha -reductase 2 activity was normal in g enital skin fibroblasts from the phenotypic male patient but undetectable i n genital skin fibroblasts from the phenotypic female patient. The lack of 5 alpha -reductase 2 activity was due to absent or reduced expression of 5 alpha -reductase 2 in genital skin fibroblasts from the phenotypic female p atient. Exon and flanking intron sequences of the 5 alpha -reductase 2 gene showed no mutations in either sibling. Additional intragenic polymorphic m arker analysis gave no evidence for different inherited alleles for the 5 a lpha -reductase 2 gene in the two siblings. Therefore, the absent or reduce d expression of 5 alpha -reductase 2 is likely to be additional to the AIS. Distinct phenotypic variation in this family was caused by 5 alpha -reducta se 2 deficiency, additional to AIS. This 5 alpha -reductase deficiency is d ue to absence of expression of the 5 alpha -reductase iso-enzyme 2 as shown by molecular studies. The distinct phenotypic variation in AIS here is exp lained by differences in the availability of 5 alpha -dihydrotestosterone d uring embryonic sex differentiation.