title: Missense mutations ofMLH1andMSH2genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers.
abstract: TheMLH1andMSH2genes in DNA mismatch repair are important in the pathogenesis of gastrointestinal cancer. Recent studies of normal and alternative splicing suggest that the deleterious effects of missense mutations may in fact be splicing-related when they are located in exonic splicing enhancers (ESEs) or exonic splicing silencers (ESSs). In this study, we used ESE-finder and FAS-ESS software to analyze the potential ESE/ESS motifs of the 114 missense mutations detected in the two genes in East Asian gastrointestinal cancer patients. In addition, we used the SIFT tool to functionally analyze these mutations. The amount of the ESE losses (68) was 51.1% higher than the ESE gains (45) of all the mutations. However, the amount of the ESS gains (27) was 107.7% higher than the ESS losses (13). In total, 56 (49.1%) mutations possessed a potential exonic splicing regulator (ESR) error. Eighty-one mutations (71.1%) were predicted to be deleterious with a lower tolerance index as detected by the Sorting Intolerant from Tolerant (SIFT) tool. Among these, 38 (33.3%) mutations were predicted to be functionally deleterious and possess one potential ESR error, while 18 (15.8%) mutations were predicted to be functionally deleterious and exhibit two potential ESR errors. These may be more likely to affect exon splicing. Our results indicated that there is a strong correlation between missense mutations inMLH1andMSH2genes detected in East Asian gastrointestinal cancer patients and ESR motifs. In order to correctly understand the molecular nature of mutations, splicing patterns should be compared between wild-type and mutant samples.
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093; ; Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing 210009, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Wang
keywords: MLH1; MSH2; exonic splicing enhancer; exonic splicing silencer; gastrointestinal cancer; missense mutation