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<p>Unexplained recurrent pregnancy loss (URPL) represents a prevalent obstetric complication and remains a challenging condition with poorly understood genetic etiology. Through whole-exome sequencing of 94 URPL patients, we identified enriched <i>MLH3</i> gene mutations in five individuals (p.G1302Efs21/p.G752E, p.V741F/p.S845G, p.V1220M/p.L1339F, p.T942I/p.G1163D, p.I988M/p.A1426V), with a 5.32% mutation frequency in this cohort which significantly exceeded the general population prevalence (0-0.011%), suggesting MLH3’s potential pathogenicity in URPL. Functional characterization using a Trim-Away-mediated Mlh3 depletion model in mouse germinal vesicle (GV)-stage oocytes revealed that Mlh3 loss disrupts spindle assembly, mislocalizes the spindle assembly checkpoint kinase BubR1, and induces focal chromosomal imbalances in early embryos. These defects lead to impaired blastocyst development and a high rate (63.89%) of post-implantation pregnancy loss after embryo transfer, recapitulating human URPL in vivo. Concurrently, MLH3 knockdown in human endometrial stromal cells impaired decidualization, disrupted morphological transformation, and altered proliferation-apoptosis homeostasis, indicating defective endometrial receptivity. Together, these findings establish maternal MLH3 as a dual-function gene essential for both oocyte quality and endometrial receptivity, providing a novel mechanistic basis for its role in URPL pathogenesis.</p>

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Maternal MLH3 dysfunction drives unexplained recurrent pregnancy loss via impaired oocyte maturation and defective decidualization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Yaoqiu Wu,
  • Ting Liang,
  • Yajing Liu,
  • Liqiong Zhu,
  • Hanjie Mo,
  • Xiran Chen,
  • Xuezhe Huang,
  • Hui Li,
  • Menglan Zhu,
  • Qingxue Zhang,
  • Hui Chen,
  • Chunwei Cao

摘要

Unexplained recurrent pregnancy loss (URPL) represents a prevalent obstetric complication and remains a challenging condition with poorly understood genetic etiology. Through whole-exome sequencing of 94 URPL patients, we identified enriched MLH3 gene mutations in five individuals (p.G1302Efs21/p.G752E, p.V741F/p.S845G, p.V1220M/p.L1339F, p.T942I/p.G1163D, p.I988M/p.A1426V), with a 5.32% mutation frequency in this cohort which significantly exceeded the general population prevalence (0-0.011%), suggesting MLH3’s potential pathogenicity in URPL. Functional characterization using a Trim-Away-mediated Mlh3 depletion model in mouse germinal vesicle (GV)-stage oocytes revealed that Mlh3 loss disrupts spindle assembly, mislocalizes the spindle assembly checkpoint kinase BubR1, and induces focal chromosomal imbalances in early embryos. These defects lead to impaired blastocyst development and a high rate (63.89%) of post-implantation pregnancy loss after embryo transfer, recapitulating human URPL in vivo. Concurrently, MLH3 knockdown in human endometrial stromal cells impaired decidualization, disrupted morphological transformation, and altered proliferation-apoptosis homeostasis, indicating defective endometrial receptivity. Together, these findings establish maternal MLH3 as a dual-function gene essential for both oocyte quality and endometrial receptivity, providing a novel mechanistic basis for its role in URPL pathogenesis.