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• Androgen receptor mutations were identified in women with Müllerian duct anomalies. • In silico analysis and ACMG guidelines classified the variants' pathogenicity. • Androgen receptor mutations resulted in conformational changes of the native protein. Müllerian duct anomalies (MDAs) are congenital developmental disorders exhibiting as a variety of malformations of female reproductive tract. The identified etiology of MDAs is limited. The present study aimed to unravel the underlying genetic causes of MDAs. Rare variants in androgen receptor (AR) were called from the cohort consists of patients with MDAs and underwent whole exome sequencing (WES) at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Sanger sequencing was used to confirm the causative genetic mutations. In silico analysis were used to classify the pathogenicity of each variant. Molecular modeling and simulations were conducted to investigate the conformational changes between the wild-type (WT) and mutant proteins. A total of 3 rare heterozygous variants in AR from the MDAs cohort in our institution were identified, with unknown effects. All variants were missense mutations, including c.173A > T, c.558C > A and c.1208C > T, and were absent or rare in East Asian populations in Genome Aggregation Database and the Exome Aggregation Consortium Database. According to the American College of Medical Genetics and Genomics guidelines, c.1208C > T variant was classified as likely pathogenic, while the other two were variants of uncertain significance. During molecular dynamics simulations, WT and mutant proteins all reached stable status according to root-mean-square variance. Values of radius of gyration showed that Q58L and S186R protein would be more compact than WT, while the structure of A403V became looser. Despite, in comparison with WT, the number of hydrogen bonds increased in Q58L, while decreased in the other two variants. Furthermore, the solvent-accessible surface area diminished in Q58L and A403V while enlarged in S186R proteins, when compared with WT. To our knowledge, this is the first report regarding the association of AR mutation and MDAs. The identification of these variants, predicted to damage the structure and function of AR protein, not only expanded the mutational spectrum of causative genes of MDAs, but provide novel molecular genetic reference for future studies. [ABSTRACT FROM AUTHOR]

Complete androgen insensitivity syndrome (CAIS) is a relatively rare X-linked disorder caused by androgen receptor gene (AR) mutations that result in complete impairment of genital virilisation. In these individuals, no müllerian derivatives are usually found; however, several sporadic cases of CAIS with müllerian remnants have been reported. In this paper, we report two novel point mutations of the AR gene resulting in two cases of CAIS with incomplete müllerian regression. Molecular studies of cases 1 and 2 showed novel missense mutations of the AR gene, with a methionine to threonine substitution at codon 749 (base 2608 T→C) in exon 5 and a methionine to lysine substitution at codon 787 (base 2722 T→A) in exon 6. Both patients received bilateral gonadectomy and inguinal hernia repair. The excised gonads proved to be testes with incomplete regression of the müllerian structures. Conclusion:müllerian structures can be present in androgen insensitivity syndrome and the presence of a uterus therefore does not exclude this disorder. Further study of these patients may promote a better understanding of the pathogenesis. [ABSTRACT FROM AUTHOR]