Comparative in silico analyses and experimental validation of novel splice site and missense mutations in the genes MLH1 and MSH2

  • Beate Betz
  • Stephan Theiss
  • Murat Aktas
  • Carolin Konermann
  • Timm O. Goecke
  • Gabriela Möslein
  • Heiner Schaal
  • Brigitte Royer-Pokora
Original Paper


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.


HNPCC MLH1 MSH2 Splice site mutations Missense mutations Exonic splicing enhancer 



This work was supported by DFG grant SCHA 909/2-2 (H. Schaal) and by grants from the Stiftung für AIDS-Forschung, Düsseldorf (H. Schaal) and Deutsche Krebshilfe Nr. 1070/2.

Supplementary material

432_2009_643_MOESM1_ESM.pdf (17 kb)
Supplementary material 1 (PDF 17 kb)


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Beate Betz
    • 1
  • Stephan Theiss
    • 2
  • Murat Aktas
    • 1
    • 3
  • Carolin Konermann
    • 4
  • Timm O. Goecke
    • 1
  • Gabriela Möslein
    • 5
  • Heiner Schaal
    • 4
  • Brigitte Royer-Pokora
    • 1
  1. 1.Institut fuer HumangenetikUniversitaetsklinikum DuesseldorfDuesseldorfGermany
  2. 2.RESULT GmbHDuesseldorfGermany
  3. 3.Institut fuer Transplantationsdiagnostik und ZelltherapeutikaUniversitaetsklinikum DuesseldorfDuesseldorfGermany
  4. 4.Institut fuer VirologieUniversitaetsklinikum DuesseldorfDuesseldorfGermany
  5. 5.Klinik fuer ChirurgieSt Josefs-Hospital Bochum-LindenBochumGermany

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