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MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential

Yiyang Wang,  Yu Qi,  Keyan Xu,  Shuyan Tang,  Luyi Tan,  Bingying Xu,  Ying Wang,  Shuxian Zhang,  Yang Zou,  Yuan Gao,  Chunmei Zhang,  Xin Liang,  Xue Jiao,  Shidou Zhao,  Han Zhao,  Shixuan Wang,  Yingying Qin,  Ting Guo,  Zi-Jiang Chen

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文章导航 > Journal of Genetics and Genomics  > 2025 > 优先出版
Yiyang Wang, Yu Qi, Keyan Xu, Shuyan Tang, Luyi Tan, Bingying Xu, Ying Wang, Shuxian Zhang, Yang Zou, Yuan Gao, Chunmei Zhang, Xin Liang, Xue Jiao, Shidou Zhao, Han Zhao, Shixuan Wang, Yingying Qin, Ting Guo, Zi-Jiang Chen. MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential[J]. 遗传学报. doi: 10.1016/j.jgg.2025.12.005
引用本文: Yiyang Wang, Yu Qi, Keyan Xu, Shuyan Tang, Luyi Tan, Bingying Xu, Ying Wang, Shuxian Zhang, Yang Zou, Yuan Gao, Chunmei Zhang, Xin Liang, Xue Jiao, Shidou Zhao, Han Zhao, Shixuan Wang, Yingying Qin, Ting Guo, Zi-Jiang Chen. MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential[J]. 遗传学报. doi: 10.1016/j.jgg.2025.12.005
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Yiyang Wang, Yu Qi, Keyan Xu, Shuyan Tang, Luyi Tan, Bingying Xu, Ying Wang, Shuxian Zhang, Yang Zou, Yuan Gao, Chunmei Zhang, Xin Liang, Xue Jiao, Shidou Zhao, Han Zhao, Shixuan Wang, Yingying Qin, Ting Guo, Zi-Jiang Chen. MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential[J]. Journal of Genetics and Genomics. doi: 10.1016/j.jgg.2025.12.005
Citation: Yiyang Wang, Yu Qi, Keyan Xu, Shuyan Tang, Luyi Tan, Bingying Xu, Ying Wang, Shuxian Zhang, Yang Zou, Yuan Gao, Chunmei Zhang, Xin Liang, Xue Jiao, Shidou Zhao, Han Zhao, Shixuan Wang, Yingying Qin, Ting Guo, Zi-Jiang Chen. MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential[J]. Journal of Genetics and Genomics. doi: 10.1016/j.jgg.2025.12.005
shu

MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential

doi: 10.1016/j.jgg.2025.12.005

  • a. State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China;

  • b. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China;

  • c. Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China;

  • d. Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China;

  • e. Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China;

  • f. Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China;

  • g. Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China;

  • h. State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China;

  • i. International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China;

  • j. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, 250014, China;

  • k. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China;

  • l. Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China;

  • m. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200135, China;

  • n. Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China

基金项目: 

Basic Science Center Program of NSFC (31988101)

Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371).

National Natural Science Foundation of China (82421004, 82125014, 32070847, 82401921)

Program for Excellent Young Scholars of Shandong Province (ZR2022YQ69)

the Key Project of Natural Science Foundation of Shandong Province (ZR202105250005)

Natural Science Foundation of Shandong Province (ZR2024QH562)

Developmental Program of China (2022YFC2703800, 2022YFC2703000)

We would like to thank all the participants who took part in the study. This work was supported by the National Key Research &

详细信息
    通讯作者:

    Shixuan Wang,E-mail:shixuanwang@tjh.tjmu.edu.cn

    Yingying Qin,E-mail:qinyingying1006@163.com

    Ting Guo,E-mail:gtlyp2008@126.com

MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential

  • a. State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China;

  • b. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China;

  • c. Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China;

  • d. Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China;

  • e. Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China;

  • f. Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China;

  • g. Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China;

  • h. State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China;

  • i. International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China;

  • j. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, 250014, China;

  • k. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China;

  • l. Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China;

  • m. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200135, China;

  • n. Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China

Funds: 

Basic Science Center Program of NSFC (31988101)

Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371).

National Natural Science Foundation of China (82421004, 82125014, 32070847, 82401921)

Program for Excellent Young Scholars of Shandong Province (ZR2022YQ69)

the Key Project of Natural Science Foundation of Shandong Province (ZR202105250005)

Natural Science Foundation of Shandong Province (ZR2024QH562)

Developmental Program of China (2022YFC2703800, 2022YFC2703000)

We would like to thank all the participants who took part in the study. This work was supported by the National Key Research &

    摘要
  • 摘要:

    Meiotic DNA double-strand break (DSB) formation is pivotal for oocyte development, regulating both ovarian reserve and oocyte developmental potential. Mutations in DSB formation genes have been associated with premature ovarian insufficiency (POI) and adverse pregnancy outcomes in women. Whole exome sequencing in 1530 POI patients across two Chinese cohorts identifies loss-of-function variants in the DSB formation gene, MEI4, enriched in POI. These MEI4 variants impair DSB formation in vitro and reveal a previously unrecognized function of the MEI4 C-terminus in stabilizing the MEI4–REC114 subcomplex on the chromosome axes. Additionally, Mei4Arg356*/Arg356* mice display severe defects in DSB formation, leading to massive apoptosis in oocytes triggered by the HORMAD1-dependent synapsis checkpoint in late prophase I. The few mutant oocytes surviving past the checkpoint exhibit low developmental potential, characterized by complete early embryonic arrest due to aneuploidy. Notably, heterozygous Mei4+/Arg356* mice show intermediate follicle depletion and embryonic development arrest consistent with the phenotype of heterozygous POI and preimplantation embryonic arrest, suggesting a haploinsufficiency effect. This study defines the impacts of MEI4 mutation on oocyte quantity and quality, which can guide genetic diagnosis and intervention in patients with POI and early embryonic arrest, especially those with mutations in meiotic DSB formation genes.

    Abstract:

    Meiotic DNA double-strand break (DSB) formation is pivotal for oocyte development, regulating both ovarian reserve and oocyte developmental potential. Mutations in DSB formation genes have been associated with premature ovarian insufficiency (POI) and adverse pregnancy outcomes in women. Whole exome sequencing in 1530 POI patients across two Chinese cohorts identifies loss-of-function variants in the DSB formation gene, MEI4, enriched in POI. These MEI4 variants impair DSB formation in vitro and reveal a previously unrecognized function of the MEI4 C-terminus in stabilizing the MEI4–REC114 subcomplex on the chromosome axes. Additionally, Mei4Arg356*/Arg356* mice display severe defects in DSB formation, leading to massive apoptosis in oocytes triggered by the HORMAD1-dependent synapsis checkpoint in late prophase I. The few mutant oocytes surviving past the checkpoint exhibit low developmental potential, characterized by complete early embryonic arrest due to aneuploidy. Notably, heterozygous Mei4+/Arg356* mice show intermediate follicle depletion and embryonic development arrest consistent with the phenotype of heterozygous POI and preimplantation embryonic arrest, suggesting a haploinsufficiency effect. This study defines the impacts of MEI4 mutation on oocyte quantity and quality, which can guide genetic diagnosis and intervention in patients with POI and early embryonic arrest, especially those with mutations in meiotic DSB formation genes.

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  • 收稿日期:  2025-11-13
  • 录用日期:  2025-12-12
  • 修回日期:  2025-12-09
  • 网络出版日期:  2025-12-18

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