title: Comparative in silico analyses and experimental validation of novel splice site and missense mutations in the genes MLH1 and MSH2.
abstract: Hereditary non-polyposis colorectal cancer, an autosomal dominant predisposition to colorectal cancer and other malignancies, is caused by inactivating mutations of DNA mismatch repair genes, mainly MLH1 and MSH2. Missense mutations affect protein structure or function, but may also cause aberrant splicing, if located within splice sites (ss) or cis-acting sequences of splicing regulatory proteins, i.e., exonic splicing enhancers or exonic splicing silencers. Despite significant progress of ss scoring algorithms, the prediction for the impact of mutations on splicing is still unsatisfactory. For this study, we assessed ten ss and nine missense mutations outside ss in MLH1 and MSH2, including eleven newly identified mutations, and experimentally analyzed their effect at the RNA level. We additionally tested and compared the reliability of several web-based programs for the prediction of splicing outcome for these mutations.
authors: Institut fuer Humangenetik, Universitaetsklinikum Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany.
authors: Beate
authors: B
authors: Betz
authors: Stephan
authors: S
authors: Theiss
authors: Murat
authors: M
authors: Aktas
authors: Carolin
authors: C
authors: Konermann
authors: Timm O
authors: TO
authors: Goecke
authors: Gabriela
authors: G
authors: Möslein
authors: Heiner
authors: H
authors: Schaal
authors: Brigitte
authors: B
authors: Royer-Pokora
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000465:Algorithms; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D022821:RNA Splice Sites; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein