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Abstract：
Many mismatch repair (MMR) gene disease-causing mutations identified in cancer patients result in aberrant messenger RNA (mRNA) splicing. However, mRNA assay interpretation can be complicated by the existence of naturally occurring alternative mRNA transcripts, most of which have not been formally described or fully characterized. Here, we provide a comprehensive catalogue of all MMR transcripts described to date, and a review of MMR nucleotide variants associated with an apparent upregulation of alternatively spliced transcripts. This work sets reference starting points for designing and interpreting MMR RNA analyses. Our database and literature searches retrieved 30 MLH1, 22 MSH2, 4 MSH6 and 9 PMS2 alternative transcripts, many predicted to introduce premature termination codons. Furthermore, we collected information on 66 MLH1, 24 MSH2 and 6 PMS2 nucleotide variants reported to be associated with altered expression of at least one of these alternative transcripts, and in many instances reported as splicing mutations. This review shows that there are many alternatively spliced MMR transcripts, which have potential to confound interpretation of splicing assays. These findings highlight the need to perform RNA analysis of patients systematically in parallel with control individuals, and call for the implementation of quantitative assessment of transcript levels for informed interpretation of mRNA assays.
摘要：
在癌症患者中鉴定的许多错配修复(MMR)基因致病突变导致异常的信使RNA(mRNA)剪接。然而,mRNA测定解释可能是复杂的天然存在的替代mRNA转录物的存在，其中大多数没有被正式描述或完全描述。这里,我们提供了迄今为止描述的所有MMR转录本的全面目录，以及与可变剪接转录本的明显上调相关的MMR核苷酸变体的综述。这项工作为设计和解释MMRRNA分析设定了参考起点。我们的数据库和文献检索检索到30个MLH1，22个MSH2，4个MSH6和9个PMS2替代转录本，许多人预测会引入过早终止密码子。此外，我们收集了66个MLH1，24个MSH2和6个PMS2核苷酸变异的信息，据报道这些变异与至少一个这些替代转录本的表达改变有关。在许多情况下被报道为剪接突变。这篇综述表明，有许多选择性剪接的MMR转录本，有可能混淆剪接测定的解释。这些发现强调了对患者与对照个体并行进行系统RNA分析的必要性。并呼吁对转录物水平进行定量评估，以对mRNA测定进行知情解释。
