XRCC2 mutation causes meiotic arrest, azoospermia and infertility.
XRCC2 mutation causes meiotic arrest, azoospermia and infertility.
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XRCC2 突变会导致减数分裂停滞、无精症和不育。
DOI：
10.1136/jmedgenet-2017-105145
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发表时间：
2018-09
影响因子：
4
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Yang Y;Guo J;Dai L;Zhu Y;Hu H;Tan L;Chen W;Liang D;He J;Tu M;Wang K;Wu L
背景减数分裂同源重组（HR）在配子发生中起重要作用。在大多数真核生物中，减数分裂HR由两种重组酶系统介导：普遍存在的RAD 51和减数分裂特异性DMC 1。在RAD 51介导的HR系统中，RAD 51和5个RAD 51旁系同源物对于RAD 51的正常功能是必需的，但RAD 51在人类减数分裂中的作用尚不清楚。敲除小鼠中的Rad 51或任何Rad 51部分表现出胚胎致死性。我们调查了一个有减数分裂阻滞、无精子症和不育但无其他异常的家系。方法对一个家系进行基因纯合性定位和全外显子测序。通过使用CRISPR/Cas9系统创建携带相关突变的动物模型。结果在该家系中发现一个RAD 51基因上的1bp纯合性突变（c.41T>C/p.Leu14Pro），即XRCC 2。我们在127例非梗阻性无精子症男性队列中未检测到任何XRCC 2隐性突变。通过CRISPR/Cas9方法成功产生具有Xrcc 2-c.T41C/p.Leu14Pro突变的敲入小鼠。纯合子存活，并表现出减数分裂停滞，无精子症，卵巢早衰和不育。结论基因敲入小鼠复制了一个导致人类减数分裂阻滞和不育的XRCC 2隐性突变。我们的研究结果揭示了一个新的孟德尔遗传实体，并提供了一个实验模型的RAD 51-HR基因缺陷的哺乳动物减数分裂。
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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DOI：
10.1126/science.1219379
发表时间：
2012-09-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cloud V;Chan YL;Grubb J;Budke B;Bishop DK
通讯作者：
Bishop DK
影响因子：
4
作者：
Ayhan, Ozgecan;Balkan, Mahmut;Tolun, Aslihan
通讯作者：
Tolun, Aslihan
影响因子：
14.9
作者：
Cartwright, R;Tambini, CE;Thacker, J
通讯作者：
Thacker, J
DOI：
10.1073/pnas.111005698
发表时间：
2001-07-17
影响因子：
11.1
作者：
Masson, JY;Stasiak, AZ;West, SC
通讯作者：
West, SC
影响因子：
9.8
作者：
Li, Quan;Wang, Kai
通讯作者：
Wang, Kai