XRCC2 mutation causes meiotic arrest, azoospermia and infertility.

Abstract

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 <i>Rad51</i> or any <i>Rad51</i> paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities. 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. We identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a <i>RAD51</i> paralogue, namely, <i>XRCC2</i>, in the consanguineous family. We did not detect any <i>XRCC2</i> recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with <i>Xrcc2</i>-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. A <i>XRCC2</i> 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.