Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein
Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein
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DOI：
10.1053/j.gastro.2006.08.044
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发表时间：
2006-11-01
期刊：
影响因子：
29.4
通讯作者：
Nystrom, Minna
中科院分区：
文献类型：
--
作者：
Ollila, Saara;Sarantaus, Laura;Nystrom, Minna
背景与目的：错配修复基因MLH1、MSH2和MSH6的遗传有害突变易导致遗传性非息肉病性结直肠癌。一个主要的诊断挑战是难以评估错义突变的致病性。先前我们发现MSH6中的大多数错义变异不会损害MMR能力，并且与无或低癌症易感性相关，而在MLH1中，功能研究区分了具有严重缺陷的非截断突变与那些没有或轻微受损的蛋白表达或功能。本研究旨在评估MSH2遗传错义突变的致病性。方法：检测15个MSH2突变蛋白的表达/稳定性、MSH2/MSH6相互作用和修复效率，其中包括14个氨基酸替换和1个帧内缺失。遗传、生化指标与临床指标具有相关性。进行比较序列分析，以评估序列同源性作为预测功能结果的工具的价值。结果：所研究的MSH2突变均未破坏该蛋白或消除MSH2/MSH6相互作用，而12个突变损害了该蛋白的修复能力。比较序列分析正确预测了14个氨基酸取代中的13个的功能研究。结论：12个突变的解释是致病的，2个突变是非致病的，1个突变的解释是矛盾的。虽然没有MSH2染色与错义突变的致病性之间存在显著的相关性，但其致病性不能通过表型特征明确区分。与MSH6和MLH1不同，MSH2错义突变的致病性总是与突变蛋白的修复能力受损有关。
Background & Aims: inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. Methods: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. Results: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. Conclusions: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein.