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Bi-allelic MEI1 variants cause meiosis arrest and non-obstructive azoospermia

Journal of Human Genetics volume 68, pages 383–392 (2023)Cite this article

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Abstract

Non-obstructive azoospermia (NOA) is characterized by the failure of sperm production due to testicular disorders and represents the most severe form of male infertility. Growing evidences have indicated that gene defects could be the potential cause of NOA via genome-wide sequencing approaches. Here, bi-allelic deleterious variants in meiosis inhibitor protein 1 (MEI1) were identified by whole-exome sequencing in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. Furthermore, the missense variant (c.T1585A) was assumed to affect the interaction between MEI1 and its partners via bioinformatic analysis. Collectively, our findings provide direct genetic and functional evidences that bi-allelic variants in MEI1 could cause defective DSBs homoeostasis and meiotic chromosome synapsis, which subsequently lead to meiosis arrest and male infertility. Thus, our study deepens our knowledge of the role of MEI1 in male fertility and provides a novel insight to understand the genetic aetiology of NOA.

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Data availability

The datasets used and/or analyzed during the current study available from the corresponding author, (CY), on reasonable request.

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Acknowledgements

We would like to thank Yan Hong, Wei Chen, Xiaobo Wang, Cunzhong Deng, Hongfang Sun, and Jianxiong Zhang for the coordinated study recruitment and sample collection.

Funding

This work was supported by National Natural Science Foundation of China (82001530, 81903417, 81871215, and 81971368), Clinical Research Innovation Plan of Shanghai General Hospital (KD007-ly01, CTCCR-C04), Clinical Research Plan of SHDC (SHDC2020CR3077B), and the Key Project of Research and Development of Ningxia Hui Autonomous Region of China (2020BFH02002), and Shanghai Sailing Program (20YF1439500 and 20YF1453700).

Author information

Author notes

  1. These authors contributed equally: Yuxiang Zhang, Na Li, Zhiyong Ji.

Authors and Affiliations

  1. 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

    Yuxiang Zhang, Haowei Bai, Ruhui Tian, Peng Li, Erlei Zhi, Yuhua Huang, Zheng Li & Chencheng Yao

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Na Li

  3. CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China

    Na Li

  4. University of Chinese Academy of Sciences, Beijing, 100049, China

    Na Li

  5. Reproductive Medical Department, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Zhiyong Ji

  6. State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, 211100, China

    Ningjing Ou & Jingpeng Zhao

  7. Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Yaqin Han

  8. The Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, 17 Shougouling Road, Guangzhou, 510620, China

    Jing Zhang

  9. The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Yuchuan Zhou

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  1. Yuxiang Zhang
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Contributions

Conceptualization: YXZ, NL, ZYJ, CCY, ZL and YCZ; Data curation: HWB, RHT, PL and JPZ; Formal Analysis: ELZ, YHH, JPZ and YQH; Funding acquisition: CCY, ZL and YCZ; Investigation: NJO, HWB and JPZ; Project administration: YXZ, NL and ZYJ, Supervision: RHT, YQH and JZ; Visualization: PL and YHH; Writing – original draft: YXZ and NL; Writing – review & editing: YXZ, CCY, ZL, YCZ and JZ.

Corresponding authors

Correspondence to Jing Zhang, Yuchuan Zhou, Zheng Li or Chencheng Yao.

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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 School of Medicine (Permit Number 2020SQ199). Written informed consent was obtained from the patient and his parents for publication.

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Zhang, Y., Li, N., Ji, Z. et al. Bi-allelic MEI1 variants cause meiosis arrest and non-obstructive azoospermia. J Hum Genet 68, 383–392 (2023). https://doi.org/10.1038/s10038-023-01119-3

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