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Mutator phenotypes of common polymorphisms and missense mutations in MSH2
K Drotschmann1, A B Clark, T A Kunkel
1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Current Biology : CB
|September 2, 1999
Summary
Germline mutations in the DNA mismatch repair gene hMSH2 are linked to hereditary non-polyposis colorectal cancer (HNPCC). Even partial loss of hMSH2 function, including from polymorphisms, may increase cancer risk.
Area of Science:
- Molecular biology
- Genetics
- Cancer research
Background:
- Hereditary non-polyposis colorectal cancer (HNPCC) is linked to germline mutations in the DNA mismatch repair gene hMSH2.
- Deleterious hMSH2 mutations often cause loss of protein function, but the impact of missense mutations and polymorphisms is less clear.
Purpose of the Study:
- To investigate the functional consequences of hMSH2 missense mutations and polymorphisms.
- To determine if these variants affect DNA mismatch repair and mutation rates.
Main Methods:
- Utilized yeast strains to model human hMSH2 polymorphisms and missense mutations.
- Assessed mutation rates in yeast strains harboring equivalent variants.
Main Results:
- Yeast strains with equivalents of hMSH2 polymorphisms showed elevated mutation rates.
- Equivalents of hMSH2 missense mutations from HNPCC families and tumors also exhibited mutator effects.
- Observed distinct phenotypes, indicating differential impacts of missense mutations on MSH2 function.
Conclusions:
- Partial loss of hMSH2 function may be associated with cancer development.
- hMSH2 polymorphisms could potentially predispose individuals to disease.