Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A novel MCMDC2 variant causes meiotic arrest and non-obstructive azoospermia in a consanguineous Chinese family

Journal of Human Genetics (2025)Cite this article

Subjects

Abstract

Non-obstructive azoospermia (NOA) is often associated with genetic variants. Whole-exome sequencing (WES) has emerged as a powerful tool in studying the genetic diagnosis of NOA and to help identify novel causal gene variants. Minichromosome maintenance domain-containing 2 (MCMDC2), an atypical yet conserved MCM protein, plays a key role in meiotic recombination and the maintenance of fertility. To date, only a limited number of MCMDC2 variants have been reported. The current study identified a novel deleterious variant (c.G226T/p.Val76Phe) of MCMDC2 by WES in a patient with NOA from a consanguineous Chinese family. Bioinformatics analysis indicated that the altered amino acid is highly conserved, and the c.G226T/p.Val76Phe variant may affect the structure and function of the MCMDC2 protein. Our results provide new insights into the underlying etiology of NOA in humans, further expanding the mutant spectrum of MCMDC2.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Data availability

In our study, all data and materials are available from the corresponding author on reasonable request.

References

  1. Cerván-Martín M, Castilla JA, Palomino-Morales RJ, Carmona FD. Genetic landscape of nonobstructive azoospermia and new perspectives for the clinic. J Clin Med. 2020;9:300.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cioppi F, Rosta V, Krausz C. Genetics of azoospermia. Int J Mol Sci. 2021;22:3264.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Peña VN, Kohn TP, Herati AS. Genetic mutations contributing to non-obstructive azoospermia. Best Pr Res Clin Endocrinol Metab. 2020;34:101479.

    Article  Google Scholar 

  4. Ishiguro KI. Mechanisms of meiosis initiation and meiotic prophase progression during spermatogenesis. Mol Asp Med. 2024;97:101282.

    Article  CAS  Google Scholar 

  5. Talibova G, Bilmez Y, Ozturk S. DNA double-strand break repair in male germ cells during spermatogenesis and its association with male infertility development. DNA Repair. 2022;118:103386.

    Article  PubMed  CAS  Google Scholar 

  6. Hann MC, Lau PE, Tempest HG. Meiotic recombination and male infertility: from basic science to clinical reality? Asian J Androl. 2011;13:212–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. MacLennan M, Crichton JH, Playfoot CJ, Adams IR. Oocyte development, meiosis and aneuploidy. Semin Cell Dev Biol. 2015;45:68–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Salas-Huetos A, Tüttelmann F, Wyrwoll MJ, Kliesch S, Lopes AM, Gonçalves J, et al. Correction to: Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia. Hum Genet. 2021;140:229.

    Article  PubMed  Google Scholar 

  9. Wang Y, Chen Y, Chen J, Wang L, Nie L, Long J, et al. The meiotic TERB1-TERB2-MAJIN complex tethers telomeres to the nuclear envelope. Nat Commun. 2019;10:564.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. van der Bijl N, Röpke A, Biswas U, Wöste M, Jessberger R, Kliesch S, et al. Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest. Hum Reprod. 2019;34:2112–9.

    PubMed  Google Scholar 

  11. Bai HW, Li N, Zhang YX, Luo JQ, Tian RH, Li P, et al. Novel biallelic MCMDC2 variants were associated with meiotic arrest and nonobstructive azoospermia. Asian J Androl. 2025;27:268–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Corona G, Minhas S, Giwercman A, Bettocchi C, Dinkelman-Smit M, Dohle G, et al. Sperm recovery and ICSI outcomes in men with non-obstructive azoospermia: a systematic review and meta-analysis. Human Reprod Update. 2019;25:733–57.

    Article  Google Scholar 

  13. Xie C, Wang W, Tu C, Meng L, Lu G, Lin G, et al. Meiotic recombination: insights into its mechanisms and its role in human reproduction with a special focus on non-obstructive azoospermia. Human Reprod Update. 2022;28:763–97.

    Article  CAS  Google Scholar 

  14. Kohl KP, Jones CD, Sekelsky J. Evolution of an MCM complex in flies that promotes meiotic crossovers by blocking BLM helicase. Science. 2012;338:1363–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Finsterbusch F, Ravindranathan R, Dereli I, Stanzione M, Tränkner D, Tóth A. Alignment of homologous chromosomes and effective repair of programmed DNA double-strand breaks during mouse meiosis require the minichromosome maintenance domain containing 2 (MCMDC2) protein. PLoS Genet. 2016;12:e1006393.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kherraf ZE, Cazin C, Bouker A, Fourati Ben Mustapha S, Hennebicq S, Septier A, et al. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia. Am J Hum Genet. 2022;109:508–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Ke H, Tang S, Guo T, Hou D, Jiao X, Li S, et al. Landscape of pathogenic mutations in premature ovarian insufficiency. Nat Med. 2023;29:483–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Lillepea K, Juchnewitsch AG, Kasak L, Valkna A, Dutta A, Pomm K, et al. Toward clinical exomes in diagnostics and management of male infertility. Am J Hum Genet. 2024;111:877–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Sun SC, Kim NH. Spindle assembly checkpoint and its regulators in meiosis. Hum Reprod Update. 2012;18:60–72.

    Article  PubMed  CAS  Google Scholar 

  20. McNairn AJ, Rinaldi VD, Schimenti JC. Repair of meiotic DNA breaks and homolog pairing in mouse meiosis requires a minichromosome maintenance (MCM) paralog. Genetics. 2017;205:529–37.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patient and his family members for participating in our study.

Funding

This work was supported by the Basic research projects of central scientific research institutes, Grant/Award Number: 2023GJZD01.

Author information

Author notes

  1. These authors contributed equally: Qi Fang, Lanxi Ran.

Authors and Affiliations

  1. Department of Reproduction, Tianjin First Central Hospital, Tianjin, China

    Qi Fang, Jianyong Di, Ye Liu & Fengqin Xu

  2. Center for Genetics, National Research Institute for Family Planning, Beijing, China

    Lanxi Ran, Song Liu & Binbin Wang

  3. Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Lanxi Ran, Song Liu & Binbin Wang

  4. NHC Key Laboratory of Reproductive Health Engineering Technology Research (NRIFP), Beijing, China

    Binbin Wang

Authors
  1. Qi Fang
    View author publications

    Search author on:PubMed Google Scholar

  2. Lanxi Ran
    View author publications

    Search author on:PubMed Google Scholar

  3. Song Liu
    View author publications

    Search author on:PubMed Google Scholar

  4. Jianyong Di
    View author publications

    Search author on:PubMed Google Scholar

  5. Ye Liu
    View author publications

    Search author on:PubMed Google Scholar

  6. Fengqin Xu
    View author publications

    Search author on:PubMed Google Scholar

  7. Binbin Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

B.W. and F.X. conceived this study. Q.F. and L.R. drafted the manuscript and analyzed data. S.L., J.D. and Y.L. performed experiments and validation.

Corresponding authors

Correspondence to Fengqin Xu or Binbin Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The ethics committee of the National Research Institute for Family Planning approved this study (protocol code 2021010). The participants signed informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, Q., Ran, L., Liu, S. et al. A novel MCMDC2 variant causes meiotic arrest and non-obstructive azoospermia in a consanguineous Chinese family. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01397-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s10038-025-01397-z

Search

Advanced search

Quick links