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The hMSH2(M688R) Lynch syndrome mutation may function as a dominant negative
Juana V Martín-López1, Ysamar Barrios, Vicente Medina-Arana
1Unidad de Investigación Mixta HUC-ULL, Facultad de Medicina, Universidad de La Laguna, La Laguna, Santa Cruz de Tenerife, 38002, Spain.
Carcinogenesis
|June 29, 2012
Summary
A founder mutation in the hMSH2 gene, hMSH2(M688R), is linked to Lynch syndrome and a high incidence of central nervous system tumors. This mutation impairs DNA mismatch repair, potentially acting as a dominant negative factor.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Lynch syndrome (LS/HNPCC) is associated with mismatch repair (MMR) gene mutations.
- Some LS/HNPCC families exhibit unusual central nervous system (CNS) tumors, typical of Turcot or CMMR-D syndromes.
- The hMSH2(M688R) mutation, found in Spanish families, is a potential founder mutation for LS/HNPCC.
Purpose of the Study:
- To investigate the functional impact of the hMSH2(M688R) mutation on MMR.
- To determine if hMSH2(M688R) contributes to the observed tumor spectrum, including CNS tumors.
- To differentiate the pathogenicity of hMSH2(M688R) from the hMSH2(M688I) alteration.
Main Methods:
- In vitro analysis of hMSH2(M688R)-hMSH6 heterodimer function.
- Assessment of ATP binding and hydrolysis activity of the mutated heterodimer.
- Comparison of hMSH2(M688R) and hMSH2(M688I) heterodimers with wild-type (WT) counterparts.
Main Results:
- The hMSH2(M688R) heterodimer binds mismatched nucleotides but lacks normal ATP function.
- hMSH2(M688R) inhibits wild-type MMR in vitro and may act as a dominant negative.
- hMSH2(M688I) heterodimer shows no functional difference from WT, suggesting it is benign.
Conclusions:
- The hMSH2(M688R) mutation is a likely dominant-negative founder mutation contributing to LS/HNPCC and CNS tumors.
- Tumor expression variability and MSI in some hMSH2(M688R) carriers support a dominant-negative mechanism.
- The hMSH2(M688I) alteration is likely a non-pathogenic polymorphism.
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