• PMID: 30042186
• Gene Name: XRCC2
• Condition: Meiotic arrest, azoospermia, male infertility
• Association: Associated
• Mutation: c.41T>C/p.Leu14Pro
• Population size: 127
• Population details: 127 cases of non-obstructive azoospermia
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

Yang Y, Guo J, Dai L, Zhu Y, Hu H, Tan L, Chen W, Liang D, He J, Tu M, Wang K, Wu L.

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. CI - © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Yang, Yongjia AU - Yang Y AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - State Key Laboratory of Medical Genetics, Central South University, Changsha, China. FAU - Guo, Jihong AU - Guo J AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - State Key Laboratory of Medical Genetics, Central South University, Changsha, China. AD - Xiangya Hospital, Central South University, Changsha, China. FAU - Dai, Lei AU - Dai L AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - State Key Laboratory of Medical Genetics, Central South University, Changsha, China. AD - Xiangya Hospital, Central South University, Changsha, China. FAU - Zhu, Yimin AU - Zhu Y AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - Hunan People's Hospital, Hunan Normal University, Changsha, China. FAU - Hu, Hao AU - Hu H AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - Department of Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, China. FAU - Tan, Lihong AU - Tan L AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. FAU - Chen, Weijian AU - Chen W AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. FAU - Liang, Desheng AU - Liang D AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - State Key Laboratory of Medical Genetics, Central South University, Changsha, China. FAU - He, Jingliang AU - He J AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. AD - State Key Laboratory of Medical Genetics, Central South University, Changsha, China. FAU - Tu, Ming AU - Tu M AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China. FAU - Wang, Kewei AU - Wang K AD - The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China.