Familial Cancer

, Volume 5, Issue 2, pp 195–199 | Cite as

A ‘Nonsense’ Mutation Leads to Aberrant Splicing of hMLH1 in a German Hereditary Non-polyposis Colorectal Cancer Family

  • J. Baehring
  • C. Sutter
  • M. Kadmon
  • M. V. Knebel Doeberitz
  • J. GebertEmail author


Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germline mutations in at least four genes encoding integral components of the cellular DNA mismatch repair (MMR) system. The spectrum of genetic alterations encompasses missense- and nonsense mutations, intronic mutations affecting splice donor or acceptor sites as well as small-scale deletions and insertions. We have identified a ‘nonsense’ mutation that activates a cryptic splice site generating an in frame deletion of the last 17 codons of exon1 of the hMLH1 gene causing HNPCC in a German family. We present a comprehensive genetic analysis of this family that demonstrates important aspects of HNPCC pathogenesis.

Key words

aberrant splicing hMLH1 hMSH2 HNPCC nonsense mutation splice donor site 


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  1. 1.
    Fishel, R, Lescoe, MK, Rao, MR,  et al. 1993The human mutator gene homolog MSH2 and its association with hereditary non-polyposis colon cancerCell75102738PubMedCrossRefGoogle Scholar
  2. 2.
    Bronner, CE, Baker, SM, Morrison, PT,  et al. 1994Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancerNature36825861PubMedCrossRefGoogle Scholar
  3. 3.
    Nicolaides, NC, Papadopoulos, N, Liu, B,  et al. 1994Mutations of two PMS homologues in hereditary non-polyposis colon cancerNature3717580PubMedCrossRefGoogle Scholar
  4. 4.
    Ionov, Y, Peinado, MA, Malkhosyan, S,  et al. 1993Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesisNature36355861PubMedCrossRefGoogle Scholar
  5. 5.
    Umar, A, Boland, CR, Terdiman, JP,  et al. 2004Revised Bethesda Guidelines for hereditary non-polyposis colorectal cancer (Lynch syndrome) and microsatellite instabilityJ Natl Cancer Inst962618PubMedCrossRefGoogle Scholar
  6. 6.
    Boland, CR, Thibodeau, SN, Hamilton, SR,  et al. 1998A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancerCancer Res58524857PubMedGoogle Scholar
  7. 7.
    Papadopoulos, N, Nicolaides, NC, Wei, YF,  et al. 1994Mutation of a mutL homolog in hereditary colon cancerScience26316259PubMedGoogle Scholar
  8. 8.
    Kolodner, RD, Hall, NR, Lipford, J,  et al. 1995Structure of the human MLH1 locus and analysis of a large hereditary non-polyposis colorectal carcinoma kindred for mlh1 mutationsCancer Res552428PubMedGoogle Scholar
  9. 9.
    Kruger, S, Plaschke, J, Pistorius, S,  et al. 2002Seven novel MLH1 and MSH2 germline mutations in hereditary non-polyposis colorectal cancerHum Mutat1982PubMedCrossRefGoogle Scholar
  10. 10.
    Raschle, M, Dufner, P, Marra, G,  et al. 2002Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalphaJ Biol Chem2772181020PubMedCrossRefGoogle Scholar
  11. 11.
    Nystrom-Lahti, M, Perrera, C, Raschle, M,  et al. 2002Functional analysis of MLH1 mutations linked to hereditary non-polyposis colon cancerGenes Chromosomes Canc331607CrossRefGoogle Scholar
  12. 12.
    Venables, JP 2004Aberrant and alternative splicing in cancerCancer Res64764754PubMedCrossRefGoogle Scholar
  13. 13.
    Ginjaar, IB, Kneppers, AL, Meulen, JD,  et al. 2000Dystrophin nonsense mutation induces different levels of exon 29 skipping and leads to variable phenotypes within one BMD familyEur J Hum Genet87936PubMedCrossRefGoogle Scholar
  14. 14.
    Wehner, M, Buschhausen, L, Lamberti, C,  et al. 1997Hereditary Non-polyposis Colorectal Cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genesHum Mutat102414PubMedCrossRefGoogle Scholar
  15. 15.
    Moslein, G, Tester, DJ, Lindor, NM,  et al. 1996Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancerHum Mol Genet5124552PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • J. Baehring
    • 1
    • 3
  • C. Sutter
    • 2
    • 4
  • M. Kadmon
    • 1
  • M. V. Knebel Doeberitz
    • 2
  • J. Gebert
    • 2
    Email author
  1. 1.Department of General SurgeryUniversity of HeidelbergHeidelbergGermany
  2. 2.Division of Molecular PathologyInstitute of Pathology, University of HeidelbergHeidelbergGermany
  3. 3.Departments of Neurology and NeurosurgeryYale University School of MedicineNew HavenUSA
  4. 4.Department of Human GeneticsInstitute of Human Genetics, University of HeidelbergHeidelbergGermany

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