A novel mutation in the ligand-binding domain of the androgen receptor gene associated with scrotal hypospadias

Abstract

Objective: Scrotal hypospadias is the severe form of hypospadias with complex and elusive etiology. The androgens and the androgen receptors play a critical role in the male external genitalia development. The main objective of the study was to evaluate clinical, genetic, biochemical profiles and perform molecular testing of Androgen Receptor (AR) gene in a boy with scrotal hypospadias and micropenis. Methods: Chromosomal analyses is performed by harvesting lymphocytes from peripheral blood sample, hormonal analysis from serum and gene sequencing of AR gene from the DNA. Results: The chromosomal analysis revealed 46,XY karyotype with normal and molecular genetic testing of Androgen Receptor (AR) gene identified a novel homozygous missense mutation of single nucleotide mutation G to T at position 2702 (GenBank accession number GU784858), resulting in amino acid interchange methionine to isoleucine at codon 780 in exon 6 (Met780Ile) (GenBank Protein_id: ADD 26780). Conclusions: The nature of the novel AR mutation identified in a boy with scrotal hypospadias provides significant information due to importance of missense mutations in the ligand binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capacity, stabilization of active conformation or interaction with coactivators. The novel mutation identified in the study provides additional support to the previously reported genotype-phenotype correlations, and our finding has expanded the spectrum of known mutations of the AR gene.