The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex
| Autor: | Christopher D. Heinen, Jennifer L. Cyr, Graham D. Brown, Jennifer Stroop |
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| Rok vydání: | 2011 |
| Předmět: |
Genetics
congenital hereditary and neonatal diseases and abnormalities Cancer Research Mutation Mismatch repair complex nutritional and metabolic diseases Microsatellite instability Biology medicine.disease_cause medicine.disease digestive system diseases MSH6 Germline mutation Start codon MSH2 medicine DNA mismatch repair neoplasms Molecular Biology |
| Zdroj: | Molecular Carcinogenesis. 51:647-658 |
| ISSN: | 0899-1987 |
| Popis: | Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS. Therefore, the pathogenicity of start codon variants remains undefined. Loss of the MSH2 start codon has been predicted to result in a truncated protein translated from a downstream in-frame AUG that would lack the first 25 amino acids. We therefore purified recombinant MSH2(NΔ25)-MSH6 and MSH2(NΔ25)-MSH3 to examine their DNA lesion recognition and adenosine nucleotide processing functions in vitro. We found that the MSH2(NΔ25) mutant confers distinct biochemical defects on MSH2-MSH6, but does not have a significant effect on MSH2-MSH3. We confirmed that expression of the MSH2 c.1A>C cDNA results in the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. An in vivo MMR assay revealed a slight reduction in MMR efficiency in these cells. These data suggest that mutation of the MSH2 initiation codon, while not a strong, high-risk disease allele, may have a moderate impact on disease phenotype. |
| Databáze: | OpenAIRE |
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