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.
- XRCC2 mutation
- meiotic arrest
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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.
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