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The androgen insensitivity syndrome (AIS) is a disorder of male sexual development resulting in a wide range of clinical phenotypes. AIS is classified into two phenotypic forms: complete (CAIS) and partial (PAIS). To determine the molecular basis of the phenotypic diversity in AIS, we have studied 27 subjects (13 CAIS, 14 PAIS), spanning the full range of AIS phenotypes. We report the results of a mutation screen of the androgen receptor gene. The coding regions of the gene were amplified by the polymerase chain reaction and screened for single strand conformation polymorphisms to identify mutations. This was followed by DNA sequencing of putative mutant segments. Androgen receptor gene mutations were identified in nine CAIS and five PAIS subjects. Two of the CAIS mutations in exon A resulted in frameshifts. A third CAIS mutation resulted in the deletion of a single amino acid from the ligand binding domain of the receptor. All other mutations caused single amino acid substitutions in the ligand binding domain. These results suggest that mutations affecting the ligand binding domain of the androgen receptor are the most frequent cause of AIS, although some cases of PAIS may be the result of other, as yet undefined, genetic lesions.

Partial androgen insensitivity syndrome (PAIS) is caused by defects in the androgen receptor gene and presents with a wide range of undervirilization phenotypes. We studied the consequences of six androgen receptor ligand-binding domain mutations on receptor function in transfected cells. The mutations, Met742Ile, Met780Ile, Gln798Glu, Arg840Cys, Arg855His and Ile869Met, were identified in PAIS patients with phenotypes representing the full spectrum seen in this condition. In all cases the androgen receptor was found to be defective, suggesting that the mutation is the cause of the clinical phenotype. The Gln798Glu mutation is exceptional in that it did not cause an androgen-binding defect in our system, although the mutant receptor was defective in transactivation assays. This mutation may affect an aspect of binding not tested, or may be part of a functional subdomain of the ligand-binding domain involved in transactivation. Overall we found milder mutations to be associated with milder clinical phenotypes. There is also clear evidence that phenotype is not solely dependent on androgen receptor function. Some of the mutant receptors were able to respond to high doses of androgen in vitro, suggesting that patients carrying these mutations may be the best candidates for androgen therapy. One such mutation is Ile869Met. A patient carrying this mutation has virilized spontaneously at puberty, so in vivo evidence agrees with the experimental result. Thus a more complete understanding of the functional consequences of androgen receptor mutations may provide a more rational basis for gender assignment in PAIS.

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