A Frame-Shift Mutation of the Androgen Receptor Gene in a Patient with Receptor-Negative Complete Testicular Feminization: Comparison with a Single Base Substitution in a Receptor-Reduced Incomplete Form

Abstract

Mutations of the androgen receptor that impair the action of androgens result in abnormal male sexual development. We studied the structure of the androgen receptor gene in a patient with the receptor-negative form of complete testicular feminization and another patient with a receptor-reduced form of incomplete testicular feminization. In the subject with complete testicular feminization, the deletion of a single nucleotide occurred at nucleotide number 1893 at exon 2. The subsequent frame-shift mutation changes the sense of codon 622 from cysteine to a translational stop signal. Codon 622 is in exon 3, so the mutation predicts the synthesis of a truncated receptor that lacks the entire androgen-binding domain. Analysis of a subject with incomplete testicular feminization revealed a single substitution (CGT → CAT) at nucleotide 2675 of exon 7, resulting in the conversion of an arginine at amino acid 840 to a histidine. This mutation in the androgen-binding domain may impair, but not remove, the androgen binding to its receptor. These results suggest that the phenotypes in our subjects are due to the mutations, and that single amino acid substitution and premature termination codon can cause variably severe functional abnormalities.