The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex

Authors

  • Jennifer L. Cyr,

    1. Neag Comprehensive Cancer Center and Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut
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  • Graham D. Brown,

    1. Neag Comprehensive Cancer Center and Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut
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  • Jennifer Stroop,

    1. Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut
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  • Christopher D. Heinen

    Corresponding author
    1. Neag Comprehensive Cancer Center and Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut
    • University of Connecticut Health Center, 263 Farmington Avenue, M.C. 3101, Farmington, CT 06030-3101, USA.
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Abstract

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. © 2011 Wiley Periodicals, Inc.

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