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Influence of Eight Unclassified Missense Variants of the MLH1 Gene on Lynch Syndrome Susceptibility

机译：MLH1基因的八个未分类的错义变体对林奇综合征的敏感性

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Missense mutations in MLH1 have frequently been detected in patients with Lynch syndrome, but their genetic significance has not been extensively assessed. In this study, we attempt to evaluate the etiological role of eight MLH1 missense variants. The variants were analyzed for their ability to affect MLH1 protein interaction with its partner PMS2 in vivo employing a yeast two-hybrid system. In addition, a SIFT (sorting intolerant from tolerant) algorithm was adopted to predict the effects of amino acid substitutions. Finally, scanning of mutations in a normal Chinese population and assay of the clinical characteristics have all been taken into account. Our results demonstrated that the MLH1 variants D485E and L653R cause functional alterations of the human MutLα complex significantly. The R265C, D304V, A586P, and R755S variants affect partial interaction. The remaining two variants, N38D and L559R, could be nonfunctional polymorphisms or might affect the mismatch repair system through other mechanisms.
机译：在Lynch综合征患者中经常检测到MLH1的错义突变，但尚未对其遗传学意义进行广泛评估。在这项研究中，我们试图评估八个MLH1错义变体的病因学作用。使用酵母双杂交系统分析了这些变体在体内影响MLH1蛋白与其伴侣PMS2相互作用的能力。另外，采用SIFT（从不耐分选到不耐分）算法来预测氨基酸取代的影响。最后，已经考虑了正常中国人群中突变的扫描和临床特征的测定。我们的结果表明，MLH1变体D485E和L653R显着引起人MutLα复合体的功能改变。 R265C，D304V，A586P和R755S变体会影响部分交互。其余两个变体N38D和L559R可能是非功能性多态性，或可能通过其他机制影响错配修复系统。

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