ANDROGEN INSENSITIVITY SYNDROME DUE TO NEW MUTATIONS IN THE DNA-BINDING DOMAIN OF THE ANDROGEN RECEPTOR

Androgen insensitivity syndrome (AIS) is associated with a wide range of quantitative or qualitative defects in the androgen receptor (AR). In some patients with AIS, however, no defects are detectable in the l igand-binding properties of the AR. We have analyzed the ARs of two un related patients with this category (termed 'receptor-positive type') of AIS. Sequence analysis of these patients' AR gene revealed single a mino acid substitutions ((579)Cys(<T(G)under bar C>) --> Phe(<T(T)unde r bar C>) and (582)Phe(<T(T)under bar C>) --> Tyr(<T(A)under bar C>)) in exon B encoding the first zinc finger of the DNA-binding domain of the AR. These mutations have not been previously reported. Moreover, c otransfection assays and mobility shift assays revealed that these pat ients' mutant ARs had defective transcriptional activity of the target gene because of impaired DNA-binding ability to the androgen-responsi ve element. These findings strongly indicate that these mutations are responsible for the pathogenesis of AIS in these patients.