MOLECULAR-BASIS OF ANDROGEN INSENSITIVITY

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. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal develo pment of both internal and external male structures in 46,XY individua ls. The complete form of androgen insensitivity syndrome is characteri zed by 46,XY karyotype, external female phenotype, intra-abdominal tes tes, absence of uterus and ovaries, blindly ending vagina, and gynecom astia. There is also a group of disorders of androgen action that resu lt from partial impairment of androgen receptor function. Clinical ind ications can be abnormal sexual development of individuals with a pred ominant male phenotype with severe hypospadias and micropenis or of in dividuals with a predominantly female phenotype with cliteromegaly, am biguous genitalia, and gynecomastia. Complete oi gross deletions of th e androgen receptor gene have not been frequently found in persons wit h the complete androgen insensitivity syndrome, whereas point mutation s at several different sites in exons 2-8 encoding the DNA- and androg en-binding domain have been reported in both partial and complete form s of androgen androgen insensitivity with a relatively high number of mutations in two clusters in exons 5 and 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hi nge region, located between the DNA-binding domain and the ligand-bind ing domain. The X-linked condition of spinal and bulbar muscle atrophy (Kennedy's disease) is characterized by a progressive motor neuron de generation associated with signs of androgen insensitivity and inferti lity. The molecular cause of spinal and bulbar muscle atrophy is art e xpanded length (>40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.