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Novel disease loci
Original article
XRCC2 mutation causes meiotic arrest, azoospermia and infertility
  1. Yongjia Yang1,2,
  2. Jihong Guo1,2,3,
  3. Lei Dai1,2,3,
  4. Yimin Zhu1,4,
  5. Hao Hu1,5,
  6. Lihong Tan1,
  7. Weijian Chen1,
  8. Desheng Liang1,2,
  9. Jingliang He1,2,
  10. Ming Tu1,
  11. Kewei Wang1,
  12. Lingqian Wu1,2
  1. 1 The Laboratory of Genetics and Metabolism, Hunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, University of South China, Changsha, China
  2. 2 State Key Laboratory of Medical Genetics, Central South University, Changsha, China
  3. 3 Xiangya Hospital, Central South University, Changsha, China
  4. 4 Hunan People’s Hospital, Hunan Normal University, Changsha, China
  5. 5 Department of Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, China
  1. Correspondence to Dr Yongjia Yang, Laboratory of Genetics and Metabolism, HunanChildren’s Research Institute (HCRI), Hunan Children’s Hospital, University of South China, Changsha, Hunan 410007, China; yongjia727{at}aliyun.com and Dr Lingqian Wu, State Key Laboratory of Medical Genetics Central South University Changsha China; wulingqian{at}sklmg.edu.cn

Abstract

Background Meiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.

Methods Homozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.

Results We identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.

Conclusion A XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

  • RAD51
  • XRCC2 mutation
  • meiotic arrest
  • infertility

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2017-105145

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    Footnotes

    • YY and JG contributed equally.

    • Contributors YJY and LQW designed the research. YJY, JHG, LD, YMZ, HH, LHT, WJC, JHG, MT, KWW performed the sample collection and the research. YJY, JHG and LD performed the bioinformatics analysis. YJY and LQW analysed the experimental data and wrote the paper.

    • Funding This work was supported by grants from the National Natural Science Foundation of China (31501017, to YJY), the Key Nature Science Foundation of Hunan Children’s Hospital (2015-0002, to YJY), the National Natural Science Foundation of China (81771599, to LQW), and the Key Laboratory fund of Hunan Province (2018TP1028, to YYJ).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Hunan Children’s Hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.