An androgen receptor mutation in the direct vicinity of the proposed C-terminal alpha-helix of the ligand binding domain containing the AF-2 transcriptional activating function core is associated with complete androgen insensitivity

Subjects with androgen insensitivity syndromes (AIS) are characterized by a 46, XY karyotype, presence of testes, normal or elevated androgen levels i n blood, and impairment of the usual response to androgens associated with various abberrations of male differentiation and virilization ranging from slightly undervirilized men to phenotypic females. Here we describe a novel proline to serine mutation in codon 892 (exon 8) of the androgen receptor in a patient with complete androgen insensitivity. The mutation is located in the direct vicinity of the proposed C-terminal alpha-helix of the ligand binding domain containing the AF-2 transcriptional activating function cor e. Investigation of androgen binding in cultured testicular fibroblasts of the patient revealed a reduced AR binding capacity (11 fmol/mg protein) and a highly elevated K-d value (3.1 nM) in comparison to control genital skin fibroblasts. Cotransfection studies with an androgen-responsive reporter g ene revealed a diminished transactivation property of the mutant androgen r eceptor. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.