RESUMEN
BACKGROUND: Androgens and androgen receptor (AR) are critical regulators of the masculinization process in male sexual development. The absence of a functioning AR results in the development of the androgen insensitivity syndrome (AIS), a rare disorder of sexual development (DSD) characterized by the external genitalia feminization, gynecomastia, and impaired spermatogenesis. OBJECTIVE: To determine the AR gene mutations associated with male DSD in four unrelated Vietnamese patients. METHODS: To detect the disease-causing mutations, whole exome sequencing (WES) was performed on four patients diagnosed with AIS. Sanger sequencing was then used for validation of the identified mutations. Finally, 12 web-based tools, three-dimensional protein modeling software, and the guidelines issued by the American College of Medical Genetics and Genomics were used to assess the potential pathogenicity of these mutations. RESULTS: Four distinct novel mutations, namely c.1834T > A (p.Cys612Ser), c.2122 C > G (p.Leu708Val), c.2630T > G (p.Phe877Cys), and c.2641 C > A (p.Leu881Met) in the AR gene, were identified in four AIS patients using WES. The in silico analysis results revealed that the Cys612, Leu708, Phe877, and Leu881 sites are important for an appropriate response to androgens of the AR, and mutation at these sites can have adverse effects on the AR functions, androgen-AR interaction, and AR signaling pathway. CONCLUSIONS: WES and in silico analyses strongly suggested that four novel AR mutations are pathogenic and have led to the development of AIS in the four Vietnamese patients under consideration.
