Germline hMLH1 promoter mutation in a Newfoundland HNPCC kindred

Clin Genet. 2003 Sep;64(3):220-7. doi: 10.1034/j.1399-0004.2003.t01-1-00110.x.


Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant form of inherited predisposition to colorectal and other malignancies. It is associated with mutations in DNA mismatch-repair genes, especially hMSH2 and hMLH1. Management of HNPCC families is improved if the underlying mutation in each family can be discovered. We describe a Newfoundland kindred, meeting the Amsterdam Criteria for HNPCC, in which a mutation in the promoter region of the hMLH1 gene co-segregates with the disease phenotype. The -42C > T mutation is within a putative Myb proto-oncogene binding site. Using electrophoretic mobility shift assays, we demonstrated that the mutated Myb binding sequence is less effective in binding nuclear proteins than the wild-type promoter sequence. Using in vivo transfection experiments in HeLa cells, we further demonstrated that the mutated promoter has only 37% of the activity of the wild-type promoter in driving the expression of a reporter gene. The average age of onset in six family members affected with colorectal cancer is 62 years, which is substantially later than the typical age of onset in HNPCC families. This is consistent with a substantial decrease, but not total elimination, of mismatch repair function in affected members of this family. This is the first report of a heritable hMLH1 promoter mutation in any HNPCC family.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenocarcinoma / epidemiology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adult
  • Age of Onset
  • Base Pair Mismatch
  • Base Sequence
  • Binding Sites
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Repair / genetics
  • Female
  • Genes, Reporter
  • Germ-Line Mutation
  • HeLa Cells
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics*
  • Newfoundland and Labrador / epidemiology
  • Nuclear Proteins
  • Pedigree
  • Polymorphism, Single-Stranded Conformational
  • Promoter Regions, Genetic / genetics*
  • Proto-Oncogene Proteins c-myb / metabolism
  • Transcription, Genetic


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myb
  • MutL Protein Homolog 1