A novel Arg615Ser mutation of androgen receptor DNA-binding domain in three 46,XY sisters with complete androgen insensitivity syndrome and bilateral inguinal hernia

Abstract

Objective: To present clinical, genetic, biochemical and molecular findings in a family with three sisters with Complete Androgen Insensitivity Syndrome (CAIS) and bilateral inguinal hernia. Design: Case report. Setting: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, India; Centre for Cellular and Molecular Biology, Hyderabad, India. Patient(s): A family with four sisters of female phenotype, three of whom have CAIS and bilateral inguinal hernia. Their parents also were screened. Intervention(s): Chromosomal analyses by harvesting lymphocytes from peripheral blood sample; hormonal analysis from serum; gene sequencing. Main Outcome Measure(s): Karyotype, testosterone, follicle-stimulating hormone and luteinizing hormone evaluation, sex-determining region Y (SRY) and Androgen Receptor (AR) gene sequencing. Result(s): In three sisters of karyotype 46, XY, we found a novel mutation of the single nucleotide transition C to A at position 2205 (GenBank accession number GU784857), resulting in amino acid interchange arginine to serine at codon 615 in exon 3 [R615S] (GenBank Protein_id ADD26779.1). The mother (46, XX) is a heterozygous carrier, and the fourth sister (46, XX) and father (46, XY) are normal. Conclusion(s): We report a novel missense mutation in exon 3 of the androgen receptor gene. The nature of the mutation presented is in the highly conserved DNA-binding domain of the AR gene, implicating it in the phenotypes observed with severe undervirilization in three sisters.