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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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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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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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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DOI: https://doi.org/10.1038/s10038-023-01172-y