Mutations in the androgen receptor (AR) gene result in a wide range of
phenotypes of the androgen insensitivity syndrome (AIS). Inter- and
intrafamilial differences in the phenotypic expression of identical AR
mutations are known, suggesting modifying factors in establishing the
phenotype. Two 46,XY siblings with partial AIS sharing the same AR gene
mutation, R846H, but showing very different phenotypes are studied. Their
parents are first cousins. One sibling with grade 5 AIS was raised as a
girl; the other sibling with grade 3 AIS was raised as a boy. In both
siblings serum levels of hormones were measured; a sex hormone-binding
globulin (SHBG) suppression test was completed; and mutation analysis of
the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was
performed. Furthermore, 5alpha-reductase 2 expression and activity in
genital skin fibroblasts were investigated, and the 5alpha-reductase 2
gene was sequenced. The decrease in SHBG serum levels in a SHBG
suppression test did not suggest differences in androgen sensitivity as
the cause of the phenotypic variation. Also, androgen binding
characteristics of the AR, AR expression levels, and the phosphorylation
pattern of the AR on hormone binding were identical in both siblings.
However, 5alpha-reductase 2 activity was normal in genital skin
fibroblasts from the phenotypic male patient but undetectable in genital
skin fibroblasts from the phenotypic female patient. The lack of
5alpha-reductase 2 activity was due to absent or reduced expression of
5alpha-reductase 2 in genital skin fibroblasts from the phenotypic female
patient. Exon and flanking intron sequences of the 5alpha-reductase 2 gene
showed no mutations in either siblin