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Published on: August 15, 2019
Two novel AMHR2 gene variants in monozygotic twins with persistent Müllerian duct syndrome: A case report and
Hong Chen1, Peng Lin1, Xin Yuan1
1Department of Endocrinology, Genetics and Metabolism, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, China.
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.
Insights
Persistent Müllerian duct syndrome (PMDS) in males is linked to novel AMHR2 gene variants. These variants impair anti-Müllerian hormone signaling, impacting development and providing insights into PMDS.
Area of Science:
- Genetics
- Endocrinology
- Developmental Biology
Background:
- Persistent Müllerian duct syndrome (PMDS) is a rare congenital disorder where Müllerian duct derivatives persist in genetically male individuals.
- Mutations in anti-Müllerian hormone (AMH) and its receptor type II (AMHR2) are known causes, but functional studies are limited.
Observation:
- A Chinese Han family with identical twins exhibiting PMDS was studied.
- Whole-exome sequencing identified two novel missense variants in the AMHR2 gene: c.118G>C [p.(Gly40Arg)] and c.1222G>C [p.(Ala408Pro)].
Findings:
- The AMHR2 p.Gly40Arg variant demonstrated reduced binding affinity for AMH.
- The AMHR2 p.Ala408Pro variant was found to disrupt the kinase domain structure.
- Both identified AMHR2 variants significantly diminished the signaling activity of the TGFβ/BMP pathway.
Implications:
- These findings identify novel AMHR2 variants associated with PMDS.
- Understanding these molecular defects can improve clinical evaluation and diagnosis of PMDS.
- This research deepens the comprehension of the genetic and molecular underpinnings of PMDS.
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