Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers
Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers
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DOI：
10.1086/378819
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发表时间：
2003-11-01
影响因子：
9.8
通讯作者：
Amos, CI
中科院分区：
文献类型：
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作者：
Gorlov, IP;Gorlova, OY;Amos, CI
我们迫切需要理解为什么错义突变是有害的。错义突变的有害作用通常归因于它们对一级氨基酸序列和蛋白质结构的影响。然而，最近的一些研究表明，一些错义突变是有害的，因为它们干扰顺式作用剪接元件-所谓的“外显子剪接增强子”（ESEs）。目前尚不清楚是否与错义突变相关的有害影响是常见的。我们已经评估了共定位的致病性错义突变（发现在受影响的个人）与高分ESE图案在人类错配修复基因hMSH 2和hMLH 1。我们发现，致病性错义突变的hMSH 2和hMLH 1基因位于ESE网站显着更频繁地比预期的。致病性错义突变也倾向于降低ESE评分，从而导致更高的剪接缺陷倾向。相反，非致病性错义突变（在未受影响的个体中发现的多态性）和无义突变相对于ESE位点随机分布。ESE位点错义突变的观察频率和预期频率的比较表明，hMSH 2中大于或等于20%的突变的致病作用是由于ESE位点的破坏和剪接干扰所致。同样，hMLH 1基因中大于或等于16%的错义突变的致病作用与ESE有关。致病性错义突变与ESE位点的共定位强烈表明它们的致病作用与剪接有关。
There is a critical need to understand why missense mutations are deleterious. The deleterious effects of missense mutations are commonly attributed to their impact on primary amino acid sequence and protein structure. However, several recent studies have shown that some missense mutations are deleterious because they disturb cis-acting splicing elements-so-called "exonic splicing enhancers" (ESEs). It is not clear whether the ESE-related deleterious effects of missense mutations are common. We have evaluated colocalization of pathogenic missense mutations (found in affected individuals) with high-score ESE motifs in the human mismatch-repair genes hMSH2 and hMLH1. We found that pathogenic missense mutations in the hMSH2 and hMLH1 genes are located in ESE sites significantly more frequently than expected. Pathogenic missense mutations also tended to decrease ESE scores, thus leading to a higher propensity for splicing defects. In contrast, nonpathogenic missense mutations (polymorphisms found in unaffected individuals) and nonsense mutations are distributed randomly in relation to ESE sites. Comparison of the observed and expected frequencies of missense mutations in ESE sites shows that pathogenic effects of greater than or equal to20% of mutations in hMSH2 result from disruption of ESE sites and disturbed splicing. Similarly, pathogenic effects of greater than or equal to16% of missense mutations in the hMLH1 gene are ESE related. The colocalization of pathogenic missense mutations with ESE sites strongly suggests that their pathogenic effects are splicing related.