title: Msh2 deficiency increases the mutation frequency in all parts of the mouse colon.
abstract: The Msh2 DNA mismatch repair gene is one of five genes implicated in the pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC). To address the possible mechanisms of the site-specific occurrence of HNPCC, the effect of Msh2 deficiency on mutations in different parts of the colon was investigated using the BC-1(lacI)/Msh2 double transgenic mouse. Compared to the Msh2(+/+) mice, Msh2(-/-) mice had an 8-9-fold increase of mutation frequency (MF) in the lacI gene from the cecum and the proximal and distal colon. The mutational spectra were also significantly different between Msh2(+/+) and Msh2(-/-) mice, with a significant increase in the frequency of -1 frameshifts and G:C-->A:T base substitutions in the repair-deficient mice. However, in spite of the site-specific predisposition of HNPCC in humans, we found no significant difference in the MF or mutation spectrum between the three parts of the colon in Msh2(+/+), Msh2(+/-), or Msh2(-/-) mice. In addition, 11 independent mutants harboring complex mutations within the lacI gene were recovered in the Msh2(-/-) mice. Interestingly, while the Msh2(+/-) mice displayed an overall MF similar to that observed in the wild-type mice, sequencing revealed a significantly different mutational spectrum between Msh2(+/+) and Msh2(+/-) mice, mainly characterized by an increase in -1 frameshifts. Due to the prevalence of frameshift mutations in HNPCC patients, this haploinsufficiency effect of the Msh2 gene in safeguarding genomic integrity may have important implications for human carrier status.
authors.affiliation: Centre for Biomedical Research, Department of Biology, University of Victoria, Victoria, BC, Canada.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhang
authors.forename: Ruth
authors.initials: R
authors.lastname: Lloyd
authors.forename: Gregory
authors.initials: G
authors.lastname: Bowden
authors.forename: Barry W
authors.initials: BW
authors.lastname: Glickman
authors.forename: Johan G
authors.initials: JG
authors.lastname: de Boer
mesh_terms: D000818:Animals; D002432:Cecum / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein