Molecular basis of androgen receptor diseases

All androgens act through a single intracellular androgen receptor (AR) whi ch 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. Alth ough CAIS is the best known phenotype, recent studies from our laboratory a nd elsewhere show that malfunction of the AR is associated with man) androg en-regulated diseases or conditions that cross traditional clinical discipl ines ranging from paediatrics (ambiguous genitalia), gynaecology (primary a menorrhoea), urology (prostate cancer), neurology (spinal bulbar muscular a trophy), reproductive medicine (male infertility), orthopedics (rheumatoid arthritis), oncology (breast cancer) and dermatology (hirsutism, baldness a nd acne). Of particular interest are the roles that polymorphic CAG trinucl eotide repeat tracts and subtle mutations in the AR ligand-binding domain h ave in the aetiology of male infertility and prostate cancer, two condition s affecting large numbers of patients. Novel mechanisms of pathogenesis hav e been uncovered in these cases, and they involve defective protein-protein interactions with coregulator molecules:such as TIF2 (transcriptional inte rmediary factor 2). Knowledge of the critical role that the AR plays in the pathogenesis of these diverse conditions has led to improved diagnostic me thods and successful therapy.