9.9
CiteScore
7.1
Impact Factor
Turn off MathJax
Article Contents
Article Navigation >  Journal of Genetics and Genomics  > 2025  > Accepted Manuscript

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

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 &

  • Received Date: 2025-11-13
  • Accepted Date: 2025-12-12
  • Rev Recd Date: 2025-12-09
    • Available Online: 2025-12-18
    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.

    • FullText(HTML)
  • loading
    • References(48)
  • Bai, L., Li, P., Xiang, Y., Jiao, X., Chen, J., Song, L., Liang, Z., Liu, Y., Zhu, Y., Lu, L.Y., 2024. BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes. Proc. Natl. Acad. Sci. U. S. A. 121, e2401386121.
    Baker, C.L., Petkova, P., Walker, M., Flachs, P., Mihola, O., Trachtulec, Z., Petkov, P.M., Paigen, K., 2015. Multimer formation explains allelic suppression of PRDM9 recombination hotspots. PLoS. Genet. 11, e1005512.
    Boekhout, M., Karasu, M.E., Wang, J., Acquaviva, L., Pratto, F., Brick, K., Eng, D.Y., Xu, J., Camerini-Otero, R.D., Patel, D.J., et al., 2019. REC114 partner ANKRD31 controls number, timing, and location of meiotic DNA breaks. Mol. Cell 74, 1053-1068.
    Borner, G.V., Cha, R.S., 2015. Induction and analysis of synchronous meiotic yeast cultures. Cold Spring Harb. Protoc. 2015, 908-913.
    Burgoyne, P.S., Mahadevaiah, S.K., Turner, J.M., 2009. The consequences of asynapsis for mammalian meiosis. Nat. Rev. Genet. 10, 207-216.
    Claeys Bouuaert, C., Pu, S., Wang, J., Oger, C., Daccache, D., Xie, W., Patel, D.J., Keeney, S., 2021. DNA-driven condensation assembles the meiotic DNA break machinery. Nature 592, 144-149.
    Daccache, D., De Jonge, E., Liloku, P., Mechleb, K., Haddad, M., Corthaut, S., Sterckx, Y.G., Volkov, A.N., Claeys Bouuaert, C., 2023. Evolutionary conservation of the structure and function of meiotic Rec114-Mei4 and Mer2 complexes. Genes. Dev. 37, 535-553.
    Daniel, K., Lange, J., Hached, K., Fu, J., Anastassiadis, K., Roig, I., Cooke, H.J., Stewart, A.F., Wassmann, K., Jasin, M., et al., 2011. Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1. Nat. Cell. Biol. 13, 599-610.
    Dereli, I., Telychko, V., Papanikos, F., Raveendran, K., Xu, J., Boekhout, M., Stanzione, M., Neuditschko, B., Imjeti, N.S., Selezneva, E., et al., 2024. Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes. Nat. Commun. 15, 2941.
    Duncan, F.E., Gerton, J.L., 2018. Mammalian oogenesis and female reproductive aging. Aging (Albany NY) 10, 162-163.
    Fakhro, K.A., Elbardisi, H., Arafa, M., Robay, A., Rodriguez-Flores, J.L., Al-Shakaki, A., Syed, N., Mezey, J.G., Abi Khalil, C., Malek, J.A., et al., 2018. Point-of-care whole-exome sequencing of idiopathic male infertility. Genet. Med. 20, 1365-1373.
    Guo, T., Zhao, S., Zhao, S., Chen, M., Li, G., Jiao, X., Wang, Z., Zhao, Y., Qin, Y., Gao, F., et al., 2017. Mutations in MSH5 in primary ovarian insufficiency. Hum. Mol. Genet. 26, 1452-1457.
    Guzeloglu-Kayisli, O., Lalioti, M.D., Aydiner, F., Sasson, I., Ilbay, O., Sakkas, D., Lowther, K.M., Mehlmann, L.M., Seli, E., 2012. Embryonic poly(A)-binding protein (EPAB) is required for oocyte maturation and female fertility in mice. Biochem. J. 446, 47-58.
    Hao, M., Pu, W., Li, Y., Wen, S., Sun, C., Ma, Y., Zheng, H., Chen, X., Tan, J., Zhang, G., et al., 2021. The HuaBiao project: whole-exome sequencing of 5000 Han Chinese individuals. J. Genet. Genomics. 48, 1032-1035.
    Huang, C., Guo, T., Qin, Y., 2021. Meiotic recombination defects and premature ovarian insufficiency. Front. Cell. Dev. Biol. 9, 652407.
    Kauppi, L., Barchi, M., Lange, J., Baudat, F., Jasin, M., Keeney, S., 2013. Numerical constraints and feedback control of double-strand breaks in mouse meiosis. Genes. Dev. 27, 873-886.
    Ke, H., Tang, S., Guo, T., Hou, D., Jiao, X., Li, S., Luo, W., Xu, B., Zhao, S., Li, G., et al., 2023. Landscape of pathogenic mutations in premature ovarian insufficiency. Nat. Med. 29, 483-492.
    Kogo, H., Tsutsumi, M., Ohye, T., Inagaki, H., Abe, T., Kurahashi, H., 2012. HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes. Genes Cells 17, 439-454.
    Krajnik, K., Mietkiewska, K., Skowronska, A., Kordowitzki, P., Skowronski, M.T., 2023. Oogenesis in women: from molecular regulatory pathways and maternal age to stem cells. Int. J. Mol. Sci. 24, 6837.
    Kumar, R., Bourbon, H.M., de Massy, B., 2010. Functional conservation of Mei4 for meiotic DNA double-strand break formation from yeasts to mice. Genes. Dev. 24, 1266-1280.
    Kumar, R., Ghyselinck, N., Ishiguro, K., Watanabe, Y., Kouznetsova, A., Hoog, C., Strong, E., Schimenti, J., Daniel, K., Toth, A., et al., 2015. MEI4-a central player in the regulation of meiotic DNA double-strand break formation in the mouse. J. Cell. Sci. 128, 1800-1811.
    Kumar, R., Oliver, C., Brun, C., Juarez-Martinez, A.B., Tarabay, Y., Kadlec, J., de Massy, B., 2018. Mouse REC114 is essential for meiotic DNA double-strand break formation and forms a complex with MEI4. Life. Sci. Alliance 1, e201800259.
    Lane, S., Kauppi, L., 2019. Meiotic spindle assembly checkpoint and aneuploidy in males versus females. Cell. Mol. Life. Sci. 76, 1135-1150.
    Laroussi, H., Juarez-Martinez, A.B., Le Roy, A., Boeri Erba, E., Gabel, F., de Massy, B., Kadlec, J., 2023. Characterization of the REC114-MEI4-IHO1 complex regulating meiotic DNA double-strand break formation. EMBO. J. 42, e113866.
    MacLennan, M., Crichton, J.H., Playfoot, C.J., Adams, I.R., 2015. Oocyte development, meiosis and aneuploidy. Semin. Cell. Dev. Biol. 45, 68-76.
    Man, L., Lustgarten Guahmich, N., Vyas, N., Tsai, S., Arazi, L., Lilienthal, D., Schattman, G., Rosenwaks, Z., James, D., 2022. Ovarian reserve disorders, can we prevent them? A Review. Int. J. Mol. Sci. 23, 15426.
    Marze, N.A., Roy Burman, S.S., Sheffler, W., Gray, J.J., 2018. Efficient flexible backbone protein-protein docking for challenging targets. Bioinformatics (Oxford, England) 34, 3461-3469.
    Nagaoka, S.I., Hassold, T.J., Hunt, P.A., 2012. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 13, 493-504.
    Nguyen, N.M.P., Ge, Z.J., Reddy, R., Fahiminiya, S., Sauthier, P., Bagga, R., Sahin, F.I., Mahadevan, S., Osmond, M., Breguet, M., et al., 2018. Causative mutations and mechanism of androgenetic hydatidiform moles. Am. J. Hum. Genet. 103, 740-751.
    Nore, A., Juarez-Martinez, A.B., Clement, J., Brun, C., Diagouraga, B., Laroussi, H., Grey, C., Bourbon, H.M., Kadlec, J., Robert, T., et al., 2022. TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks. Nat. Commun. 13, 7048.
    Pan, Z., Wang, W., Wu, L., Yao, Z., Wang, W., Chen, Y., Gu, H., Dong, J., Mu, J., Zhang, Z., et al., 2024. Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility. Hum. Genet. 143, 1049-1060.
    Picelli, S., Bjorklund, A.K., Faridani, O.R., Sagasser, S., Winberg, G., Sandberg, R., 2013. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods 10, 1096-1098.
    Practice Committee of the American Society for Reproductive Medicine, 2020. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil. Steril. 114, 1151-1157.
    Qin, Y., Zhang, F., Chen, Z.J., 2019. BRCA2 in ovarian development and function. N. Engl. J. Med. 380, 1086.
    Reichman, R., Alleva, B., Smolikove, S., 2017. Prophase I: preparing chromosomes for segregation in the developing oocyte. Results Probl. Cell. Differ. 59, 125-173.
    Rinaldi, V.D., Bolcun-Filas, E., Kogo, H., Kurahashi, H., Schimenti, J.C., 2017. The DNA damage checkpoint eliminates mouse oocytes with chromosome synapsis failure. Mol. Cell 67, 1026-1036.
    Stanzione, M., Baumann, M., Papanikos, F., Dereli, I., Lange, J., Ramlal, A., Trankner, D., Shibuya, H., de Massy, B., Watanabe, Y., et al., 2016. Meiotic DNA break formation requires the unsynapsed chromosome axis-binding protein IHO1 (CCDC36) in mice. Nat. Cell. Biol. 18, 1208-1220.
    The, E.G.G.o.P.O.I., Webber, L., Davies, M., Anderson, R., Bartlett, J., Braat, D., Cartwright, B., Cifkova, R., de Muinck Keizer-Schrama, S., Hogervorst, E., et al., 2016. ESHRE Guideline: management of women with premature ovarian insufficiency. Human Reprod. 31, 926-937.
    Turner, J.M., 2015. Meiotic silencing in mammals. Annu. Rev. Genet. 49, 395-412.
    Turner, J.M., Mahadevaiah, S.K., Fernandez-Capetillo, O., Nussenzweig, A., Xu, X., Deng, C.X., Burgoyne, P.S., 2005. Silencing of unsynapsed meiotic chromosomes in the mouse. Nat. Genet. 37, 41-47.
    Wang, Guo, T., Ke, H., Zhang, Q., Li, S., Luo, W., Qin, Y., 2021. Pathogenic variants of meiotic double strand break (DSB) formation genes PRDM9 and ANKRD31 in premature ovarian insufficiency. Genet. Med. 23, 2309-2315.
    Wang, W., Dong, J., Chen, B., Du, J., Kuang, Y., Sun, X., Fu, J., Li, B., Mu, J., Zhang, Z., et al., 2020. Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest. J. Med. Genet. 57, 187-194.
    Wang, Y., Zhai, B., Tan, T., Yang, X., Zhang, J., Song, M., Tan, Y., Yang, X., Chu, T., Zhang, S., et al., 2021b. ESA1 regulates meiotic chromosome axis and crossover frequency via acetylating histone H4. Nucleic. Acids. Res. 49, 9353-9373.
    Xie, C., Wang, W., Tu, C., Meng, L., Lu, G., Lin, G., Lu, L.Y., Tan, Y.Q., 2022. Meiotic recombination: insights into its mechanisms and its role in human reproduction with a special focus on non-obstructive azoospermia. Hum. Reprod. Update 28, 763-797.
    Xu, S., Zhao, J., Gao, F., Zhang, Y., Luo, J., Zhang, C., Tian, R., Zhi, E., Zhang, J., Bai, F., et al., 2024. A bi-allelic REC114 loss-of-function variant causes meiotic arrest and nonobstructive azoospermia. Clin. Genet. 105, 440-445.
    Zhang, Q., Tao, C., Gao, S., Li, S., Xu, B., Ke, H., Wang, Y., Zhang, F., Qin, Y., Zhang, L., et al., 2022. Homozygous variant in KASH5 causes premature ovarian insufficiency by disordered meiotic homologous pairing. J. Clin. Endocrinol. Metab. 107, 2589-2597.
    Zhao, S., Huang, C., Yang, Y., Xu, W., Yu, Y., Wen, C., Cao, L., Gao, F., Qin, Y., Chen, Z.J., et al., 2023. DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development. J. Biol. Chem. 299, 102905.
    Zickler, D., Kleckner, N., 2015. Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harb. Perspect. Biol. 7, a016626.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索
    Get Citation
    PDF

    Article Metrics

    Article views (42) PDF downloads (0) Cited by ()
    Proportional views
    Related

    Editorial Office

    Journal of Genetics and Genomics

    京ICP备09063187号-12

    No.1, West Beichen Road, Chaoyang District, Beijing 100101, P.R.China

    +86-10-64806528+86-10-64807786jgg@genetics.ac.cn

    Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return