A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred

Complete androgen insensitivity syndrome (CAIS) is an X-linked inherited di sease caused by mutations in the androgen receptor (AR) gene. We have previ ously reported the largest kindred of CAIS, with 17 46,XY psychosexual and phenotypic females who lack secondary sexual hair. Analysis of AR binding i ndicated a receptor-negative form of complete androgen insensitivity, and D NA linkage analysis indicated that the absent binding was not caused by a l arge AR gene deletion. Using PCR-single-strand DNA conformational polymorph ism, PCR-denaturing gradient gel electrophoresis, and DNA sequencing, we ha ve identified a novel mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, where a single adenine is inserted, or equivalent ly, a GC-dinucleotide is deleted at this region of the gene. The mutation r esults in a frameshift at amino acid 60 and a premature termination of the receptor downstream of the mutation. This predicts a mutant AR with only 79 amino acids in the amino-terminal of AR protein, prohibiting binding to th e ligand, as well as the cognate DNA. The rest of the encoding regions of t he AR gene in the affected subjects are normal. These results are consisten t with previous ligand binding and DNA linkage analysis studies. This new m utation in the CAG trinucleotide area of exon 1 of the AR gene represents t he first example of a defect in a CAG repeat causing CAIS in this large kin dred. All previous reported variants in this region are changes in the numb er of triplet repeats.