MUTATIONS OF ANDROGEN RECEPTOR GENE IN ANDROGEN INSENSITIVITY SYNDROMES

The androgen receptor belongs to the family of steroid-thyroid hormone -retinoid nuclear receptors. It contains 3 major domains: a hormone-bi nding region, a DNA-binding region and an amino-terminal region. Cloni ng of the cDNA encoding the androgen receptor and elucidation of the a ndrogen receptor gene structure enabled the characterization of the mo lecular defects associated with androgen insensitivity. Mutations of t he androgen receptor in 46,XY individuals cause a spectrum of androgen insensitivity syndromes, ranging from female phenotype (testicular fe minization) to minor degrees of undervirilization or infertility. Repo rts on androgen receptor gene structure in patients with complete or p artial forms of androgen insensitivity demonstrate that gene deletions are very rare. Several categories of mutations have been reported and are reviewed in this paper. Nucleotide substitutions in the androgen- binding domain or the N-terminal region that cause insertion of premat ure termination codons result in failure to form a functional protein. Missense mutations within the androgen-binding domain are responsible for a decrease or absence of receptor-binding activity. Mutations wit hin the DNA-binding domain are associated with a positive receptor-bin ding form of androgen insensitivity. Analysis of described mutations i ndicates that they are spread throughout the gene, either associated w ith partial or complete androgen insensitivity. Furthermore, the same point mutation was reported to be associated with variable phenotypic expression of androgen insensitivity syndrome. It is thus difficult to define a genotype/phenotype relationship. However, mutations causing androgen insensitivity will certainly yield important new insights int o the molecular basis of androgen action.