Molecular basis of androgen receptor diseases

androgens act through a single intracellular androgen receptor (AR) which is encoded by a single-copy gene in the X chromosome. Disruption of the AR by genetic mutation results in complete androgen insensitivity syndrome (CAIS) and the female phenotype in otherwise healthy 46XY individuals. Although CAIS is the best known phenotype, recent studies from our laboratory and elsewhere show that malfunction of the AR is associated with many androgen-regulated diseases or conditions that cross traditional clinical disciplines ranging from paediatrics (ambiguous genitalia), gynaecology (primary amenorrhoea), urology (prostate cancer), neurology (spinal bulbar muscular atrophy), reproductive medicine (male infertility), orthopedics (rheumatoid arthritis), oncology (breast cancer) and dermatology (hirsutism, baldness and acne). Of particular interest are the roles that polymorphic CAG trinucleotide repeat tracts and subtle mutations in the AR ligand-binding domain have in the aetiology of male infertility and prostate cancer, two conditions affecting large numbers of patients. Novel mechanisms of pathogenesis have been uncovered in these cases, and they involve defective protein-protein interactions with coregulator molecules such as TIF2 (transcriptional intermediary factor 2). Knowledge of the critical role that the AR plays in the pathogenesis of these diverse conditions has led to improved diagnostic methods and successful therapy.