2. Academic Validation
  3. XRCC2 mutation causes meiotic arrest, azoospermia and infertility

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

  • J Med Genet. 2018 Sep;55(9):628-636. doi: 10.1136/jmedgenet-2017-105145.
Yongjia Yang # 1 2,  Jihong Guo # 1 2 3,  Lei Dai 1 2 3,  Yimin Zhu 1 4,  Hao Hu 1 5,  Lihong Tan 1,  Weijian Chen 1,  Desheng Liang 1 2,  Jingliang He 1 2,  Ming Tu 1,  Kewei Wang 1,  Lingqian Wu 1 2
Affiliations

Affiliations

  • 1 The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, China.
  • 2 State Key Laboratory of Medical Genetics, Central South University, Changsha, China.
  • 3 Xiangya Hospital, Central South University, Changsha, China.
  • 4 Hunan People's Hospital, Hunan Normal University, Changsha, China.
  • 5 Department of Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, China.
  • # Contributed equally.
PMID: 30042186 DOI: 10.1136/jmedgenet-2017-105145
Abstract

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.

Keywords

RAD51; XRCC2 mutation; infertility; meiotic arrest.

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