PDF(Pubmed)
Abstract：
Lynch syndrome is caused by inactivating variants in DNA mismatch repair genes, namely MLH1, MSH2, MSH6 and PMS2. We have investigated five MLH1 and one MSH2 variants that we have identified in Turkish and Tunisian colorectal cancer patients. These variants comprised two small deletions causing frameshifts resulting in premature stops which could be classified pathogenic (MLH1 p.(His727Profs*57) and MSH2 p.(Thr788Asnfs*11)), but also two missense variants (MLH1 p.(Asn338Ser) and p.(Gly181Ser)) and two small, in-frame deletion variants (p.(Val647-Leu650del) and p.(Lys678_Cys680del)). For such small coding genetic variants, it is unclear if they are inactivating or not. We here provide clinical description of the variant carriers and their families, and we performed biochemical laboratory testing on the variant proteins to test if their stability or their MMR activity are compromised. Subsequently, we compared the results to in-silico predictions on structure and conservation. We demonstrate that neither missense alteration affected function, while both deletion variants caused a dramatic instability of the MLH1 protein, resulting in MMR deficiency. These results were consistent with the structural analyses that were performed. The study shows that knowledge of protein function may provide molecular explanations of results obtained with functional biochemical testing and can thereby, in conjunction with clinical information, elevate the evidential value and facilitate clinical management in affected families.
摘要：
Lynch综合征是由DNA错配修复基因的变异失活引起的,即MLH1、MSH2、MSH6和PMS2。我们研究了在土耳其和突尼斯结直肠癌患者中发现的5种MLH1和1种MSH2变体。这些变体包括两个小的缺失，导致移码，导致过早停止，可以归类为致病性（MLH1p。（His727Profs*57）和MSH2p。（Thr788Asnfs*11）），还有两个错义变体（MLH1p。（Asn338Ser）和p。（Gly181Ser））和两个小的，框内删除变体(p.（Val647-Leu650del）和p。（Lys678_Cys680del））。对于如此小的编码遗传变异，目前尚不清楚它们是否失活。我们在这里提供变异携带者及其家族的临床描述，我们对变异蛋白进行了生化实验室测试，以测试其稳定性或MMR活性是否受损。随后，我们将结果与结构和保护方面的计算机预测进行了比较。我们证明没有错义改变影响功能，虽然两种缺失变体都导致了MLH1蛋白的严重不稳定性，导致MMR缺乏。这些结果与所进行的结构分析一致。该研究表明，蛋白质功能的知识可以为功能生化测试获得的结果提供分子解释，结合临床信息，提高证据价值，促进受影响家庭的临床管理。
