Two novel AMHR2 gene variants in monozygotic twins with persistent Müllerian duct syndrome: A case report and functional study

BACKGROUND: Persistent Müllerian duct syndrome (PMDS) is an autosomal recessive congenital abnormality in which Müllerian derivatives, uterus, cervix, upper two‐thirds of the vagina, and fallopian tubes persist in otherwise normally virilized males. Mutations in anti‐Müllerian hormone (AMH) and AMH receptor type II (AMHR2) genes have been identified as causative. However, functional experimental analysis of AMHR2 or AMH variants that cause PMDS is still lacking. MATERIALS AND METHODS: A Chinese Han family affected by PMDS was identified. To assess the history and clinical manifestations of PMDS, physical, operational, ultrasonographical, pathological, and other examinations were performed on family members. The variant screening was conducted using trio whole‐exome sequencing (trio WES) and Sanger sequencing. Complementation‐based NanoLuciferase Binary Technology (NanoBiT) was used to examine the interaction between AMH and AMHR2 variants in vivo. The effect of the two variants on the transcriptional activity of the TGFβ/BMP pathway was evaluated using a luciferase assay. RESULTS: Classic phenotypic manifestations of PMDS in a pair of identical twins were described and confirmed by genetic sequence analysis. Molecular studies revealed two novel variants c.118G > C [p.(Gly40Arg)], c.1222G > C [p.(Ala408Pro)] in the AMHR2 gene. The AMHR2 p.Gly40Arg variant reduces its ability to bind to AMH, while the p.Ala408Pro variant alters the kinase domain structure. Both variants significantly reduce TGFβ/BMP signaling. CONCLUSION: Two missense AMHR2 variants associated with PMDS were identified. These findings provide novel insights toward better clinical evaluation and further understanding of the molecular basis of PMDS.