Department of Endocrinology, Genetics and Metabolism, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, China.
Mol Genet Genomic Med. 2022 Aug;10(8):e1999. doi: 10.1002/mgg3.1999. Epub 2022 Jun 2.
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.
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.
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.
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.
持续性 Müllerian 管发育不全（PMDS）是一种常染色体隐性先天性异常，在这种异常中，Müllerian 衍生物、子宫、宫颈、阴道上 2/3 段和输卵管在其他方面正常男性中持续存在。抗 Müllerian 激素（AMH）和 AMH 受体 II 型（AMHR2）基因突变已被确定为病因。然而，导致 PMDS 的 AMHR2 或 AMH 变体的功能实验分析仍然缺乏。
确定了一个受 PMDS 影响的汉族家庭。为了评估 PMDS 的病史和临床表现，对家庭成员进行了体格、手术、超声、病理等检查。采用三体外显子组测序（trio WES）和 Sanger 测序对变异进行筛选。采用基于互补的 NanoLuciferase Binary Technology（NanoBiT）技术在体内检测 AMH 和 AMHR2 变体之间的相互作用。通过荧光素酶测定评估两种变体对 TGFβ/BMP 通路转录活性的影响。
描述并通过遗传序列分析证实了一对同卵双胞胎中 PMDS 的典型表型表现。分子研究揭示了 AMHR2 基因中的两个新变异 c.118G>C[p.(Gly40Arg)]，c.1222G>C[p.(Ala408Pro)]。AMHR2 p.Gly40Arg 变体降低了与 AMH 的结合能力，而 p.Ala408Pro 变体改变了激酶结构域结构。这两种变体都显著降低了 TGFβ/BMP 信号。
鉴定出与 PMDS 相关的两个错义 AMHR2 变体。这些发现为更好的临床评估和进一步了解 PMDS 的分子基础提供了新的见解。
