FUNCTIONAL-ANALYSIS OF 6 ANDROGEN RECEPTOR MUTATIONS IDENTIFIED IN PATIENTS WITH PARTIAL ANDROGEN INSENSITIVITY SYNDROME

Partial androgen insensitivity syndrome (PAIS) is caused by defects in the androgen receptor gene and presents with a wide range of undeviri IIIzation phenotypes. We studied the consequences of six androgen rece ptor ligand-binding domain mutations on receptor function in transfect ed cells. The mutations, Met742lle, Met780lle, Gln798Glu, Arg840Cys, A rg855His and Ile869Met, were identified in PAIS patients with phenotyp es 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 mutatio n is exceptional in that it did not cause an androgen-binding defect i n our system, although the mutant receptor was defective in transactiv ation assays. This mutation may affect an aspect of binding not tested , or may be part of a functional subdomain of the ligand-binding domai n involved in transactivation, Overall we found milder mutations to be associated with milder clinical phenotypes. There is also clear evide nce that phenotype is not solely dependent on androgen receptor functi on, 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 spontaneousl y 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 gend er assignment in PAIS.