Single amino acid substitution (840Arg-->His) in the hormone-binding domain of the androgen receptor leads to incomplete androgen insensitivity syndrome associated with a thermolabile androgen receptor.

We have characterized the androgen receptor in a Japanese girl and her maternal cousin in a family with incomplete androgen insensitivity syndrome, and have investigated the molecular basis. Whole-cell androgen binding assay in cultured genital skin fibroblasts from both patients showed a normal maximum binding capacity and a normal apparent dissociation constant. However, androgen binding in fibroblasts from both patients decreased to 30% when the assay temperature was raised from 30 degrees C to 41 degrees C, indicating the presence of the thermolability of ligand binding to the androgen receptor. Sequence analysis of the coding exons of the androgen receptor gene from the patients revealed a single nucleotide substitution at position 2881 in exon G, resulting in the conversion of arginine (CGT) to histidine (CAT) at amino acid position 840 in the hormone-binding domain of the androgen receptor. The family study showed that the mothers and the maternal grandmother of the patients are heterozygous carriers for this mutation, whereas the father does not carry it, supporting the view that androgen insensitivity syndrome is an X chromosome-linked disorder. The single amino acid substitution may explain the qualitative abnormality of the androgen receptor displaying thermolability, which is thought to be the pathogenesis of incomplete androgen insensitivity syndrome in the patients.