MLH1 variants-defective DNA mismatch repair

MLH1 heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). This system assembles in a stepwise fashion, with the MutL complex recruited after the the dsDNA mismatch has been identified.<br><br>Two representative MLH1 variants are described, MLH1 HIS329PRO and MLH1 SER252TER. The MLH1 HIS329PRO variant was identified in a family that fulfilled the Amsterdam criteria (a set of diagnostic criteria used to help identify families likely to carry gene variants predisposing them to hereditary nonpolyposis colorectal cancer (HNPCC)) of HNPCC as well as its identification as a his329-to-pro germline mutation (Vasen et al., 1991, Wang et al. 1997). The mutations' pathogenic significance was supported by the identification of the same missense mutation as a somatic event ('second hit') in colonic tumors of 2 other HNPCC patients who had germline mutations at different sites of the MLH1 gene.<br><br>The MLH1 SER252TER variant was identified in a colorectal tumor cell line manifesting microsatellite instability (Papadopoulos et al, 1994). Sequence analysis of the cDNA revealed a C-to-A transversion at codon 252, resulting in the substitution of a stop codon for serine.

MLH1蛋白与PMS2蛋白异源二聚化，构成MutL alpha复合体，该复合体为后复制DNA错配修复系统（MMR）的组成部分。该系统逐步组装，在识别到双链DNA错配后，MutL复合体被招募。描述了两种代表性的MLH1变异体，即MLH1 HIS329PRO和MLH1 SER252TER变异体。MLH1 HIS329PRO变异体在一家人群中被发现，该家族符合阿姆斯特丹标准（一套用于帮助识别可能携带基因变异的家族的诊断标准，这些基因变异可能使家族成员易患遗传性非息肉性结直肠癌（HNPCC）），以及其被确认为his329到pro的生殖细胞突变（Vasen等，1991，Wang等，1997）。突变致病性得到了支持，因为在2名不同MLH1基因位点存在生殖细胞突变的HNPCC患者的结肠肿瘤中，同样识别到了该错义突变作为体细胞事件（第二次打击）。MLH1 SER252TER变异体在一例表现出微卫星不稳定的结直肠肿瘤细胞系中被发现。cDNA序列分析显示，在第252密码子处发生C到A的转换，导致丝氨酸被终止密码子取代。