Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility.
Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility.
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错配修复基因的常见变异与精子 DNA 损伤和男性不育风险增加相关
DOI：
10.1186/1741-7015-10-49
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发表时间：
2012-05-17
期刊：
影响因子：
9.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Ji G;Long Y;Zhou Y;Huang C;Gu A;Wang X
错配修复(MMR)途径在维持基因组完整性、减数分裂重组和配子发生中起着重要作用。这项研究调查了MMR基因的遗传变异是否与精子DNA损伤和男性不育风险增加有关。在1292例特发性不孕症患者和480例正常对照的病例对照研究中，我们利用SNPstream 12-plex平台选择了5个MMR基因(MLH1、MLH3、PMS2、MSH4和MSH5)上的21个标记单核苷酸多态(SNPs)并进行了基因分型。采用TdT介导的dUTP缺口末端标记法(TUNEL)检测450例精液DNA损伤水平。采用荧光共振能量转移(FRET)和免疫共沉淀技术检测功能突变体的作用。MLH1中的一个内含子SNP(Rs4647269)和PMS2中的两个非同义SNP(rs1059060，Ser775Asn)和MSH5(rs2075789，Pro29Ser)可能是无精子症或少精子症的危险因素。同时，我们还发现PMS2 rs1059060可能与精子数正常的男性不育风险有关。在精子数正常的患者中，MLH1rs4647269和PMS2rs1059060与精子DNA损伤增加相关。功能分析表明，PMS2 rs1059060可以影响MLH1与PMS2之间的相互作用。我们的结果为MMR基因的遗传多态在男性不育病因中的作用提供了证据。
The mismatch repair (MMR) pathway plays an important role in the maintenance of the genome integrity, meiotic recombination and gametogenesis. This study investigated whether genetic variations in MMR genes are associated with an increased risk of sperm DNA damage and male infertility. We selected and genotyped 21 tagging single nucleotide polymorphisms (SNPs) in five MMR genes (MLH1, MLH3, PMS2, MSH4 and MSH5) using the SNPstream 12-plex platform in a case-control study of 1,292 idiopathic infertility patients and 480 fertile controls in a Chinese population. Sperm DNA damage levels were detected with the Tdt-mediated dUTP nick end labelling (TUNEL) assay in 450 cases. Fluorescence resonance energy transfer (FRET) and co-immunoprecipitation techniques were employed to determine the effects of functional variants. One intronic SNP in MLH1 (rs4647269) and two non-synonymous SNPs in PMS2 (rs1059060, Ser775Asn) and MSH5 (rs2075789, Pro29Ser) seem to be risk factors for the development of azoospermia or oligozoospermia. Meanwhile, we also identified a possible contribution of PMS2 rs1059060 to the risk of male infertility with normal sperm count. Among patients with normal sperm count, MLH1 rs4647269 and PMS2 rs1059060 were associated with increased sperm DNA damage. Functional analysis revealed that the PMS2 rs1059060 can affect the interactions between MLH1 and PMS2. Our results provide evidence supporting the involvement of genetic polymorphisms in MMR genes in the aetiology of male infertility.
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影响因子：
4.8
作者：
Guerrette, S;Acharya, S;Fishel, R
通讯作者：
Fishel, R
DOI：
10.3109/01485019108987651
发表时间：
1991-07-01
期刊：
ARCHIVES OF ANDROLOGY
影响因子：
--
作者：
LEWIN, A;GONEN, O;SCHENKER, JG
通讯作者：
SCHENKER, JG
影响因子：
6.7
作者：
Cohen-Bacrie, Paul;Belloc, Stephanie;Benkhalifa, Moncef
通讯作者：
Benkhalifa, Moncef
影响因子：
2.8
作者：
Kumosani, T. A.;Elshal, M. F.;Abduljabar, H. S.
通讯作者：
Abduljabar, H. S.
影响因子：
64.8
作者：
NICOLAIDES, NC;PAPADOPOULOS, N;KINZLER, KW
通讯作者：
KINZLER, KW