WIDE VARIATION IN ANDROGEN RECEPTOR DYSFUNCTION IN COMPLETE ANDROGEN INSENSITIVITY SYNDROME

Androgen insensitivity syndrome (AIS) is a disorder of male sexual dif ferentiation caused by mutations in the androgen receptor (AR) gene. T he partial form (PAIS), associated with varying degrees of receptor dy sfunction, presents with a range of undevirilization phenotypes. The c omplete form (CAIS) is characterized by normal female external appeara nce at birth. In these cases the receptor is often absent or inactive. However, cases have been described where the mutant receptor concerne d has considerable residual activity in in vitro assays. Here we descr ibe the effects of five mutations, Gly750Asp, Leu762Phe, Ala765Thr, As p864Asn and Leu907Phe, identified in complete androgen insensitivity p atients. In vitro assays of mutant androgen receptors expressed in a m ammalian cell line showed that the Gly750Asp, Leu762Phe and Ala765Thr mutations cause almost complete loss of androgen-binding activity, sug gesting that these residues are critical for ligand binding. However, receptors with Asp864Asn and Leu907Phe, although defective, were capab le of considerable binding and transactivation activity. Given that so me mutations identified in PAIS patients have a more severe effect on androgen receptor function than two CAIS mutations described here, the se results provide further evidence that other factors, including gene tic background, can have a significant impact on the phenotype associa ted with a particular AR mutation. (C) 1997 Elsevier Science Ltd.