Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification.
Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification.
复制标题
MSH2 变体 N127S 和 G322D 的不确定致病性对它们的分类提出了挑战。
DOI：
10.1002/ijc.23573
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发表时间：
2008
影响因子：
6.4
通讯作者：
Nyström,Minna
中科院分区：
文献类型：
--
作者：
Ollila,Saara;DermadiBebek,Denis;Greenblatt,Marc;Nyström,Minna
遗传性非息肉病性结直肠癌(HNPCC)与错配修复(MMR)基因的胚系突变有关。然而，遗传性错义突变使诊断变得复杂，因为它们并不总是导致明确的癌症易感性。这导致了对其致病性的不同和相互矛盾的解释。在这里，我们建立了两个频繁报道的变异，MSH2 N127S和G322D的功能证据，这两个变异在文献和数据库中被描述为致病和非致病。我们报告了三种不同的功能分析结果，这些功能分析表征了这些蛋白质变体的体外生化特性。我们应用了免疫沉淀实验来评估MSH2-MSH6的相互作用，带移实验来研究错配识别和结合，以及MMR实验来研究修复效率。与野生型MSH2相比，这些实验都没有提供这些蛋白质功能降低的证据。我们的数据表明，MSH2N127S和G322Dper序列不足以触发MMR缺陷。这一点与突变携带者的不同临床表型一起表明，体内没有或只有低癌症Riskin。©2008 Wiley-Liss，Inc.
Hereditary non‐polyposis colorectal cancer (HNPCC) is associated with germline mutations in mismatch repair (MMR) genes. Inherited missense mutations, however, complicate the diagnostics because they do not always cause unambiguous predisposition to cancer. This leads to variable and contradictory interpretations of their pathogenicity. Here, we establish evidence for the functionality of the 2 frequently reported variations,MSH2N127S and G322D, which have been described both as pathogenic and non‐pathogenic in literature and databases. We report the results of 3 different functional analyses characterizing the biochemical properties of these protein variantsin vitro. We applied an immunoprecipitation assay to assess the MSH2–MSH6 interaction, a bandshift assay to study mismatch recognition and binding, and a MMR assay for repair efficiency. None of the experiments provided evidence on reduced functionality of these proteins as compared to wild‐type MSH2. Our data demonstrate thatMSH2N127S and G322Dper seare not sufficient to trigger MMR deficiency. This together with variable clinical phenotypes in the mutation carriers suggest no or only low cancer riskin vivo. © 2008 Wiley‐Liss, Inc.