ANDROGEN RECEPTOR MUTATIONS

Male sexual differentiation and development proceed under direct contr ol of androgens. Androgen action is mediated by the intracellular andr ogen receptor, which belongs to the superfamily of ligand-dependent tr anscription factors. At least three pathological situations are associ ated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA ) and prostate cancer. In the X-linked androgen insensitivity syndrome , defects in the androgen receptor gene have prevented the normal deve lopment of both internal and external male structures in 46,XY individ uals. Complete or gross deletions of the androgen receptor gene have n ot been found frequently in persons with complete androgen insensitivi ty syndrome. Point mutations at several different sites in exons 2-8 e ncoding the DNA- and androgen-binding domain, have been reported for p artial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is enco ded by the first half of exon 4. Androgen receptor gene mutations in p rostate cancer are very rare and are reported only in exons 4-8. The X -linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyg lutamine stretches in the N-terminal domain of the androgen receptor.