XRCC2 mutation causes meiotic arrest, azoospermia and infertility

Background Meiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinasesystems: ubiquitous RAD51and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51and five RAD51paralogues are essential for normal RAD51function, but the role of RAD51in human meiosisis unclear. The knockout of Rad51or any Rad51paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermiaand infertility but without other abnormalities. Methods Homozygosity mapping and whole- exome sequencingwere performed in a consanguineousfamily. An animal model carrying a related mutation was created by using a CRISPR/ Cas9system. Results We identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51paralogue, namely, XRCC2, in the consanguineousfamily. We did not detect any XRCC2recessive 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/ Cas9method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failureand infertility. Conclusion A XRCC2recessive 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.