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Identification of a missense variant of MND1 in meiotic arrest and non-obstructive azoospermia

Journal of Human Genetics volume 68, pages 729–735 (2023)Cite this article

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Abstract

Meiotic arrest is a common pathologic phenotype of non-obstructive azoospermia (NOA), yet its genetic causes require further investigation. Meiotic nuclear divisions 1 (MND1) has been proved to be indispensable for meiotic recombination in many species. To date, only one variant of MND1 has been reported associated with primary ovarian insufficiency (POI), yet there has been no report of variants in MND1 associated with NOA. Herein, we identified a rare homozygous missense variant (NM_032117:c.G507C:p.W169C) of MND1 in two NOA-affected patients from one Chinese family. Histological analysis and immunohistochemistry demonstrated meiotic arrest at zygotene-like stage in prophase I and lack of spermatozoa in the proband’s seminiferous tubules. In silico modeling demonstrated that this variant might cause possible conformational change in the leucine zippers 3 with capping helices (LZ3wCH) domain of MND1-HOP2 complex. Altogether, our study demonstrated that the MND1 variant (c.G507C) is likely responsible for human meiotic arrest and NOA. And our study provides new insights into the genetic etiology of NOA and mechanisms of homologous recombination repair in male meiosis.

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Acknowledgements

We would like to thank the proband and his family for their participation in the study. And we would like to thank Prof. Yuchuan Zhou for his kind contributions on revising this manuscript. This work was supported by National Key Research and Development Program of China (2022YFC2702701); National Natural Science Foundation of China (82001530, 82171597 and 81871215); Shanghai science and technology innovation action plan project (20Y11907600); Clinical Research Innovation Plan of Shanghai General Hospital (CTCCR-2021C17); Shanghai Sailing Program (20YF1439500); Shanghai Key Laboratory of Embryo Original Diseases (Shelab2021ZD01) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX22_0676). Molecular graphics and analyses in Fig. 3 and Table S2 were performed with UCSF ChimeraX which was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, and the three-dimensional protein structures in Fig. 3A were predicted using Colabfold on Google Colab.

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  1. These authors contributed equally: Jingpeng Zhao, Zhiyong Ji.

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211100, China

    Jingpeng Zhao, Ningjing Ou & Zheng Li

  2. Department of Andrology, Center for Men’s Health, Department of ART, Institute of Urology, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Jingpeng Zhao, Jiaqiang Luo, Yuxiang Zhang, Ningjing Ou, Haowei Bai, Ruhui Tian, Erlei Zhi, Yuhua Huang, Nachuan Liu, Zheng Li, Chencheng Yao & Peng Li

  3. Department of Reproductive Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China

    Zhiyong Ji

  4. Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China

    Guiquan Meng, Wenbin He & Yueqiu Tan

  5. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA; National Engineering and Research Center of Human Stem Cells, Changsha, 410008, China

    Wenbin He & Yueqiu Tan

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Contributions

All authors contributed to the study conception and design. PL, CCY and ZL designed the research; JPZ and ZYJ performed the research; Clinical data were collected by JQL, YXZ, NJO and HWB. Clinical samples were collected and prepared by RHT, YHH, ELZ and NCL. GQM, WBH, and YQT performed the bioinformatics analysis; JPZ, JZY, CCY, PL and ZL wrote and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zheng Li, Chencheng Yao or Peng Li.

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The authors declare no competing interests.

Ethical approval

This study was approved by the Institutional Ethical Review Committee of Shanghai General Hospital, Shanghai Jiao Tong University (Permit Number: 2020SQ199), and an informed consent of clinical data and testicular tissues for research was obtained from the donors.

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Informed consent was obtained from all individual participants included in the study.

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Zhao, J., Ji, Z., Meng, G. et al. Identification of a missense variant of MND1 in meiotic arrest and non-obstructive azoospermia. J Hum Genet 68, 729–735 (2023). https://doi.org/10.1038/s10038-023-01172-y

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