RT Journal Article
SR Electronic
T1 XRCC2 mutation causes meiotic arrest, azoospermia and infertility
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 628
OP 636
DO 10.1136/jmedgenet-2017-105145
VO 55
IS 9
A1 Yang, Yongjia
A1 Guo, Jihong
A1 Dai, Lei
A1 Zhu, Yimin
A1 Hu, Hao
A1 Tan, Lihong
A1 Chen, Weijian
A1 Liang, Desheng
A1 He, Jingliang
A1 Tu, Ming
A1 Wang, Kewei
A1 Wu, Lingqian
YR 2018
UL http://jmg.bmj.com/content/55/9/628.abstract
AB 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.