Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions

Structural changes in the androgen receptor (AR) are one of the causes of d efective spermatogenesis. We screened the AR gene of 173 infertile men with impaired spermatogenesis and identified 3 of them, unrelated, who each had a single adenine-->guanine transition that changed codon 886 in exon 8 fro m methionine to valine. This mutation was significantly associated with the severely oligospermic phenotype and was not detected in 400 control AR all eles. Despite the location of this substitution in the ligand-binding domai n (LBD) of the AR, neither the genital skin fibroblasts of the subjects nor transfected cell types expressing the mutant receptor had any androgen-bin ding abnormality. However, the mutant receptor had a consistently (approxim ately 50%) reduced capacity to transactivate each of different androgen-ind ucible reporter genes in 3 different cell lines. Deficient transactivation correlated with reduced binding of mutant AR complexes to androgen response elements. Coexpression of AR domain fragments in mammalian and yeast two-h ybrid studies suggests that the mutation disrupts interactions of the LBD w ith another LBD, with the NH2-terminal transactivation domain, and with the transcriptional intermediary factor TIF2. These data suggest chat a functi onal element centered around M886 has a role, not for ligand binding, but f or interdomain and coactivator interactions culminating in the formation of a normal transcription complex.