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A Novel Mutation in the CAG Triplet Region of Exon 1 of Androgen Receptor Gene Causes Complete Androgen Insensitivity Syndrome in a Large Kindred¹

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cornell University Medical College, New York, New York 10021.

Address all correspondence and requests for reprints to: Dr. Julianne Imperato-McGinley, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York Hospital-Cornell Medical Center, 1300 York Avenue, Box-149, Room F-263, New York, New York 10021. E-mail: jimperat{at}mail.med.cornell.edu

Complete androgen insensitivity syndrome (CAIS) is an X-linked inherited disease caused by mutations in the androgen receptor (AR) gene. We have previously reported the largest kindred of CAIS, with 17 46,XY psychosexual and phenotypic females who lack secondary sexual hair. Analysis of AR binding indicated a receptor-negative form of complete androgen insensitivity, and DNA linkage analysis indicated that the absent binding was not caused by a large AR gene deletion. Using PCR-single-strand DNA conformational polymorphism, PCR-denaturing gradient gel electrophoresis, and DNA sequencing, we have identified a novel mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, where a single adenine is inserted, or equivalently, a GC-dinucleotide is deleted at this region of the gene. The mutation results 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 the ligand, as well as the cognate DNA. The rest of the encoding regions of the AR gene in the affected subjects are normal. These results are consistent with previous ligand binding and DNA linkage analysis studies. This new mutation in the CAG trinucleotide area of exon 1 of the AR gene represents the first example of a defect in a CAG repeat causing CAIS in this large kindred. All previous reported variants in this region are changes in the number of triplet repeats.

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