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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 recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD...

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Autores principales: Yang, Yongjia, Guo, Jihong, Dai, Lei, Zhu, Yimin, Hu, Hao, Tan, Lihong, Chen, Weijian, Liang, Desheng, He, Jingliang, Tu, Ming, Wang, Kewei, Wu, Lingqian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119352/
https://www.ncbi.nlm.nih.gov/pubmed/30042186
http://dx.doi.org/10.1136/jmedgenet-2017-105145
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author Yang, Yongjia
Guo, Jihong
Dai, Lei
Zhu, Yimin
Hu, Hao
Tan, Lihong
Chen, Weijian
Liang, Desheng
He, Jingliang
Tu, Ming
Wang, Kewei
Wu, Lingqian
author_facet Yang, Yongjia
Guo, Jihong
Dai, Lei
Zhu, Yimin
Hu, Hao
Tan, Lihong
Chen, Weijian
Liang, Desheng
He, Jingliang
Tu, Ming
Wang, Kewei
Wu, Lingqian
author_sort Yang, Yongjia
collection PubMed
description 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.
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spelling pubmed-61193522018-09-04 XRCC2 mutation causes meiotic arrest, azoospermia and infertility Yang, Yongjia Guo, Jihong Dai, Lei Zhu, Yimin Hu, Hao Tan, Lihong Chen, Weijian Liang, Desheng He, Jingliang Tu, Ming Wang, Kewei Wu, Lingqian J Med Genet Novel Disease Loci 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. BMJ Publishing Group 2018-09 2018-07-24 /pmc/articles/PMC6119352/ /pubmed/30042186 http://dx.doi.org/10.1136/jmedgenet-2017-105145 Text en © 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. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Novel Disease Loci
Yang, Yongjia
Guo, Jihong
Dai, Lei
Zhu, Yimin
Hu, Hao
Tan, Lihong
Chen, Weijian
Liang, Desheng
He, Jingliang
Tu, Ming
Wang, Kewei
Wu, Lingqian
XRCC2 mutation causes meiotic arrest, azoospermia and infertility
title XRCC2 mutation causes meiotic arrest, azoospermia and infertility
title_full XRCC2 mutation causes meiotic arrest, azoospermia and infertility
title_fullStr XRCC2 mutation causes meiotic arrest, azoospermia and infertility
title_full_unstemmed XRCC2 mutation causes meiotic arrest, azoospermia and infertility
title_short XRCC2 mutation causes meiotic arrest, azoospermia and infertility
title_sort xrcc2 mutation causes meiotic arrest, azoospermia and infertility
topic Novel Disease Loci
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119352/
https://www.ncbi.nlm.nih.gov/pubmed/30042186
http://dx.doi.org/10.1136/jmedgenet-2017-105145
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