Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16

Am J Hum Genet. 1996 Feb;58(2):300-7.


Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Base Sequence
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Primers / chemistry
  • DNA Repair / genetics
  • DNA-Binding Proteins*
  • Electrophoresis, Polyacrylamide Gel
  • Europe
  • Exons / genetics
  • Female
  • Genes, Dominant
  • Germ-Line Mutation
  • Humans
  • Male
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Mutation
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Pedigree
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein