Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers.
Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers.
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胃肠道癌症患者中检测到的 MLH1 和 MSH2 基因错义突变与外显子剪接增强子和沉默子相关
DOI：
10.3892/ol.2013.1243
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发表时间：
2013-05
期刊：
影响因子：
2.9
通讯作者：
Wang YP
中科院分区：
文献类型：
--
作者：
Zhu M;Chen HM;Wang YP
MLH 1和MSH 2基因在DNA错配修复中的作用在胃肠道肿瘤的发病机制中具有重要意义。最近对正常剪接和选择性剪接的研究表明，当错义突变位于外显子剪接增强子（ESEs）或外显子剪接沉默子（ESS）时，错义突变的有害影响实际上可能与剪接相关。在这项研究中，我们使用ESE-finder和FAS-ESS软件来分析东亚胃肠癌患者中检测到的114个这两个基因的错义突变的潜在ESE/ESS基序。此外，我们使用SIFT工具对这些突变进行了功能分析。在所有突变中，ESE丢失的数量（68）比ESE增加的数量（45）高51.1%。然而，ESS增益（27）的数量比ESS损失（13）高107.7%。总共有56个（49.1%）突变具有潜在的外显子剪接调节因子（ESR）错误。预测81个突变（71.1%）是有害的，耐受性指数较低，如通过从耐受性中分选不耐受（SIFT）工具检测到的。其中，38个（33.3%）突变被预测为功能上有害的，并具有一个潜在的ESR错误，而18个（15.8%）突变被预测为功能上有害的，并表现出两个潜在的ESR错误。这些可能更有可能影响外显子剪接。我们的研究结果表明，在东亚胃肠癌患者中检测到的MLH 1和MSH 2基因的错义突变与ESR基序之间有很强的相关性。为了正确理解突变的分子本质，应比较野生型和突变体样本之间的剪接模式。
The MLH1 and MSH2 genes in DNA mismatch repair are important in the pathogenesis of gastrointestinal cancer. Recent studies of normal and alternative splicing suggest that the deleterious effects of missense mutations may in fact be splicing-related when they are located in exonic splicing enhancers (ESEs) or exonic splicing silencers (ESSs). In this study, we used ESE-finder and FAS-ESS software to analyze the potential ESE/ESS motifs of the 114 missense mutations detected in the two genes in East Asian gastrointestinal cancer patients. In addition, we used the SIFT tool to functionally analyze these mutations. The amount of the ESE losses (68) was 51.1% higher than the ESE gains (45) of all the mutations. However, the amount of the ESS gains (27) was 107.7% higher than the ESS losses (13). In total, 56 (49.1%) mutations possessed a potential exonic splicing regulator (ESR) error. Eighty-one mutations (71.1%) were predicted to be deleterious with a lower tolerance index as detected by the Sorting Intolerant from Tolerant (SIFT) tool. Among these, 38 (33.3%) mutations were predicted to be functionally deleterious and possess one potential ESR error, while 18 (15.8%) mutations were predicted to be functionally deleterious and exhibit two potential ESR errors. These may be more likely to affect exon splicing. Our results indicated that there is a strong correlation between missense mutations in MLH1 and MSH2 genes detected in East Asian gastrointestinal cancer patients and ESR motifs. In order to correctly understand the molecular nature of mutations, splicing patterns should be compared between wild-type and mutant samples.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
DOI：
10.1016/j.mrfmmm.2004.04.014
发表时间：
2004-10-04
影响因子：
2.3
作者：
Gorlov, IP;Gorlova, OY;Amos, CI
通讯作者：
Amos, CI
影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
6.2
作者：
Furukawa, T;Konishi, F;Tsukamoto, T
通讯作者：
Tsukamoto, T