MUTATIONS IN THE ANDROGEN RECEPTOR GENE CAUSING ANDROGEN RESISTANCE

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Mutations in the androgen receptor gene cause phenotypic abnormalities of male sexual development that range from a female phenotype (complete testicular feminlzation) to that of undervirilized or infertile men. These defects have previously been classified according to the abnormality identified in ligand binding studies performed in genital skin fibroblasts. Patients with absent ligand binding (receptor-binding negative), reduced levels of binding, qualitative binding abnormalities, or no ligand binding abnormality have been described. The type of ligand binding abnormality has little relationship to the clinical phenotype. Nucleotide sequence analysis of the androgen receptor coding sequence, coupled with immunoblot assays and assays of receptor function, have permitted the definition of several types of mutation in the androgen receptor gene and their effects on receptor function and abundance. In our patient population, the defects are most often due to nucleotide changes that cause either premature termination codons or single amino acid substitutions within the androgen receptor open reading frame. Premature termination codons have been identified in several coding exons and the amino acid substitutions cluster in the DNA-binding domain and two short segments of the hormone-binding domain. Despite diverse effects on the capacity of the mutant receptors to bind ligand or to target DNA sequences, functional studies and immunoblot assays indicate that the phenotypic abnormalities in patients with androgen resistance are paralleled by decreases in receptor function or abundance or both.