Novel splicing associations of hereditary colon cancer related DNA mismatch repair gene mutations.
Novel splicing associations of hereditary colon cancer related DNA mismatch repair gene mutations.
复制标题
遗传性结肠癌相关DNA错配修复基因突变的新剪接关联。
DOI：
10.1136/jmg.2003.017269
复制
发表时间：
2004
影响因子：
4
通讯作者：
Peltomäki,P
中科院分区：
文献类型：
--
作者：
Renkonen,E;Lohi,H;Järvinen,HJ;Mecklin,J-P;Peltomäki,P
遗传性非息肉性结肠癌 (HNPCC) 是一种与 DNA 错配修复 (MMR) 遗传性缺陷相关的多器官癌症综合征。迄今为止，ICG-HNPCC 突变数据库中已存入 400 多个易感突变，主要影响 MLH1 (< 50%)、MSH2 (< 40%) 和 MSH6 (< 10%)(www.nfdht.nl/)。超过一半的 HNPCC 相关 MMR 基因突变由无义或移码变化组成，导致提前终止密码子。 1 此类转录本会受到无义介导的 mRNA 衰减的影响，这是一种监视机制，其目的是保护生物体免受截短蛋白质的显性失活或功能获得影响。 2 此外，一些无义、错义甚至沉默变化可以通过引入或破坏外显子剪接增强子或外显子剪接沉默子序列来改变前 mRNA 剪接。 3-5 通过这样做，突变可能会促进它们所在的外显子的跳跃或包含。至少对于 MLH1 中的某些无义和错义突变，存在支持该机制的证据。 6 7 大多数影响剪接的突变由内含子/外显子连接处经典剪接位点的单核苷酸取代组成；这种突变在 MLH1 中尤其常见，占该基因所有种系突变的三分之一。 1在这项工作中，选择基于 RNA 的策略对遗传性非息肉病性结直肠癌家族进行突变筛查，因为之前针对同一人群的研究表明，75% 的 MLH1 和 MSH2 突变可检测为大小异常的转录本。 8 本报告重点关注已发现突变的新剪接关联。
Hereditary non-polyposis colon cancer (HNPCC) is a multi-organ cancer syndrome associated with hereditary defects in DNA mismatch repair (MMR). To date, more than 400 predisposing mutations have been deposited in the ICG-HNPCC mutation database, mostly affecting MLH1 (< 50%), MSH2 (< 40%), and MSH6 (< 10%)(www. nfdht. nl/). Over half of all HNPCC-linked MMR gene mutations consist of nonsense or frameshift changes that result in premature termination codons. 1 Such transcripts are subject to nonsense mediated mRNA decay, a surveillance mechanism whose purpose is to protect the organism against dominant negative or gain of function effects of truncated proteins. 2 Furthermore, some nonsense as well as missense and even silent changes can alter pre-mRNA splicing by introducing or disrupting exonic splicing enhancer or exonic splicing silencer sequences. 3–5 By doing so, the mutations may promote the skipping or inclusion of exons in which they are located. Evidence in support of this mechanism exists at least for certain nonsense and missense mutations in MLH1. 6 7 Most mutations that affect splicing consist of single nucleotide substitutions in the classical splice sites at intron/exon junctions; such mutations are particularly common in MLH1, constituting one third of all germline mutations in this gene. 1In this work, a strategy based on RNA was chosen for mutation screening in families with hereditary non-polyposis colorectal cancer, since a previous study on the same population indicated that 75% of MLH1 and MSH2 mutations were detectable as aberrant sized transcripts. 8 This report focuses on novel splicing associations of the mutations discovered.