DIFFERENT PHENOTYPES IN A FAMILY WITH ANDROGEN INSENSITIVITY CAUSED BY THE SAME M780I POINT MUTATION IN THE ANDROGEN RECEPTOR GENE

Mutations in the coding sequence of the androgen receptor (AR) gene re sult in a wild range of androgen insensitivity (AI) syndromes. Differe nces in the clinical expression of the same mutation in unrelated pati ents have been reported. However, this study reports for the first tim e strikingly different phenotypes among three patients within the same kindred. Two of the patients had a feminine phenotype, suggesting com plete AI, but for some pubic hair. The third subject was male with par tial AI, perineoscrotal hypospadias, and cryptorchidism. 5 alpha-reduc tase activity measured in genital skin fibroblasts and binding capacit y of the AR were higher in the male than in the two patients with fema le phenotype. Northern blot analysis of AR messenger RNA revealed a 10 -kb band of normal intensity in the three subjects. Molecular analysis of the coding sequence of the AR revealed a unique M780I mutation in exon 6, changing a methionine 780 to isoleucine in the hormone-binding domain. In conclusion, the same mutation of the AR gene in the same f amily can result in clinical phenotypes characteristic of complete or partial AI. Therefore, the molecular defect of the AR gene may not alo ne predict the phenotype in families with AI.