Molecular biology of androgen insensitivity

Androgen insensitivity syndrome (AIS) is the most common specific cause of 46,XY disorder in sex development. The androgen signaling pathway is complex but so far, the only gene linked with AIS is the androgen receptor (AR). Mutations in the AR are found in most subjects with complete AIS but in partial AIS, the rate has varied 28-73%, depending on the case selection. More than 400 different mutations in AR leading to AIS have been reported. Most mutations are missense substitutions located in the ligand binding domain of the receptor. However, when systematically screened, a substantial amount of mutations can be detected also in the N-terminal domain encoded by exon 1. Within this exon lie two trinucleotide, CAG and GGN repeat regions which are polymorphic in length. Their role in androgen insensitivity is somewhat unclear. Recent advances in protein modeling have resulted in better understanding of the mechanism of known AR mutations.