Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein

Saara Ollila, Laura Sarantaus, Reetta Kariola, Philip Chan, Heather Hampel, Elke Holinski-Feder, Finlay Macrae, Maija Kohonen-Corish, Anne-Marie Gerdes, Päivi Peltomäki, Elisabeth Mangold, Albert de la Chapelle, Marc Greenblatt, Minna Nyström

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    "Background & Aims: inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. Methods: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. Results: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. Conclusions: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein."
    Original languageEnglish
    JournalGastroenterology
    Volume131
    Pages (from-to)1408-1417
    Number of pages10
    ISSN0016-5085
    DOIs
    Publication statusPublished - 2006
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 118 Biological sciences

    Cite this

    Ollila, Saara ; Sarantaus, Laura ; Kariola, Reetta ; Chan, Philip ; Hampel, Heather ; Holinski-Feder, Elke ; Macrae, Finlay ; Kohonen-Corish, Maija ; Gerdes, Anne-Marie ; Peltomäki, Päivi ; Mangold, Elisabeth ; Chapelle, Albert de la ; Greenblatt, Marc ; Nyström, Minna. / Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. In: Gastroenterology. 2006 ; Vol. 131. pp. 1408-1417.
    @article{5b923e63ac3e44e38237ae762b5e5677,
    title = "Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein",
    abstract = "{"}Background & Aims: inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. Methods: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. Results: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. Conclusions: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein.{"}",
    keywords = "118 Biological sciences",
    author = "Saara Ollila and Laura Sarantaus and Reetta Kariola and Philip Chan and Heather Hampel and Elke Holinski-Feder and Finlay Macrae and Maija Kohonen-Corish and Anne-Marie Gerdes and P{\"a}ivi Peltom{\"a}ki and Elisabeth Mangold and Chapelle, {Albert de la} and Marc Greenblatt and Minna Nystr{\"o}m",
    year = "2006",
    doi = "10.1053/j.gastro.2006.08.044",
    language = "English",
    volume = "131",
    pages = "1408--1417",
    journal = "Gastroenterology",
    issn = "0016-5085",
    publisher = "W B SAUNDERS CO-ELSEVIER INC",

    }

    Ollila, S, Sarantaus, L, Kariola, R, Chan, P, Hampel, H, Holinski-Feder, E, Macrae, F, Kohonen-Corish, M, Gerdes, A-M, Peltomäki, P, Mangold, E, Chapelle, ADL, Greenblatt, M & Nyström, M 2006, 'Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein', Gastroenterology, vol. 131, pp. 1408-1417. https://doi.org/10.1053/j.gastro.2006.08.044

    Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. / Ollila, Saara; Sarantaus, Laura; Kariola, Reetta; Chan, Philip; Hampel, Heather; Holinski-Feder, Elke; Macrae, Finlay; Kohonen-Corish, Maija; Gerdes, Anne-Marie; Peltomäki, Päivi; Mangold, Elisabeth; Chapelle, Albert de la; Greenblatt, Marc; Nyström, Minna.

    In: Gastroenterology, Vol. 131, 2006, p. 1408-1417.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein

    AU - Ollila, Saara

    AU - Sarantaus, Laura

    AU - Kariola, Reetta

    AU - Chan, Philip

    AU - Hampel, Heather

    AU - Holinski-Feder, Elke

    AU - Macrae, Finlay

    AU - Kohonen-Corish, Maija

    AU - Gerdes, Anne-Marie

    AU - Peltomäki, Päivi

    AU - Mangold, Elisabeth

    AU - Chapelle, Albert de la

    AU - Greenblatt, Marc

    AU - Nyström, Minna

    PY - 2006

    Y1 - 2006

    N2 - "Background & Aims: inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. Methods: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. Results: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. Conclusions: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein."

    AB - "Background & Aims: inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. Methods: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. Results: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. Conclusions: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein."

    KW - 118 Biological sciences

    U2 - 10.1053/j.gastro.2006.08.044

    DO - 10.1053/j.gastro.2006.08.044

    M3 - Article

    VL - 131

    SP - 1408

    EP - 1417

    JO - Gastroenterology

    JF - Gastroenterology

    SN - 0016-5085

    ER -