Androgen receptor mutations and androgen insensitivity

The androgen receptor (AR) is a high affinity receptor protein encoded on the human X-chromosome that mediates the actions of androgens during development and in the adult. Defects in this receptor protein result in a wide range of abnormalities of male sexual development. Studies in a number of different laboratories have identified mutations of the AR gene in subjects with androgen resistance syndromes. Defects that interrupt the AR open-reading frame have been traced to a number of distinct types of genetic alterations, have been identified in widely separated segments of the AR gene, and are invariably associated with the phenotype of complete androgen insensitivity. By contrast, mutations that cause single amino acid substitutions within the AR are localized to the DNA- or ligand-binding domains of the receptor protein and have been associated with the full range of androgen resistant phenotypes. The diversity of mutations that have been identified has prompted a consideration of the relationship between AR mutation and phenotype. Analyses of AR abundance and function suggest that the phenotypic abnormalities that result from mutation of the AR reflect the extent to which AR activity is impaired in target tissues. Such decreases in AR function may be the result of the diminished receptor function, decreases in receptor concentration, or a combination of these two effects.