Complete androgen insensitivity syndrome caused by a novel mutation in the androgen receptor gene and its mechanism

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disease characterized by disorders of sex development, commonly caused by mutations of the androgen receptor (AR) gene. Herein, we identified a novel hemizygous mutation (c.2118T > A, p. Asn706Lys) of AR resulting in complete androgen insensitivity syndrome (CAIS) in twins. This missense mutation contributed to significantly decreased mRNA transcription and protein expression. In addition, structure model analysis showed that Asn706Lys resulted in loss of hydrogen bond with Asp891 and reduced protein stability. Furthermore, the mutant AR failed to bind to ligand due to the loss of hydrogen bond with dihydrotestosterone (DHT). This disrupted the translocation of AR protein from cytoplasm to nucleus after hormone stimulation. Our findings firstly demonstrated the novel mutation of c.2118T > A in AR directly caused CAIS. This contributed to expanding the AR mutational spectrum and revealed the pathogenic mechanism of AIS, as well as facilitating precise diagnosis and genetic counseling.