Functional characterization of MLH1 missense variants identified in lynch syndrome patients

Sofie Dabros Andersen, Sascha Emilie Liberti, Anne Lützen, Mark Drost, Inge Bernstein, Mef Nilbert, Mev Dominquez, Minna Nyström, Thomas van Overeem Hansen, Janus Wiese Holdal Christoffersen, Anne Charlotte Jäger, Niels de Wind, Finn Cilius Nielsen, Pernille Mathiesen Tørring, Lene Juel Rasmussen

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Resumé

    Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein–protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein–protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants
    OriginalsprogEngelsk
    TidsskriftHuman Mutation
    Vol/bind33
    Udgave nummer12
    Sider (fra-til)1647–1655
    ISSN1059-7794
    DOI
    StatusUdgivet - 2012

    Citer dette

    Andersen, S. D., Liberti, S. E., Lützen, A., Drost, M., Bernstein, I., Nilbert, M., ... Rasmussen, L. J. (2012). Functional characterization of MLH1 missense variants identified in lynch syndrome patients. Human Mutation, 33(12), 1647–1655. https://doi.org/10.1002/humu.22153
    Andersen, Sofie Dabros ; Liberti, Sascha Emilie ; Lützen, Anne ; Drost, Mark ; Bernstein, Inge ; Nilbert, Mef ; Dominquez, Mev ; Nyström, Minna ; Hansen, Thomas van Overeem ; Christoffersen, Janus Wiese Holdal ; Jäger, Anne Charlotte ; de Wind, Niels ; Nielsen, Finn Cilius ; Mathiesen Tørring, Pernille ; Rasmussen, Lene Juel. / Functional characterization of MLH1 missense variants identified in lynch syndrome patients. I: Human Mutation. 2012 ; Bind 33, Nr. 12. s. 1647–1655.
    @article{d8324c48c5cb4cda9714674510114380,
    title = "Functional characterization of MLH1 missense variants identified in lynch syndrome patients",
    abstract = "Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein–protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein–protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants",
    author = "Andersen, {Sofie Dabros} and Liberti, {Sascha Emilie} and Anne L{\"u}tzen and Mark Drost and Inge Bernstein and Mef Nilbert and Mev Dominquez and Minna Nystr{\"o}m and Hansen, {Thomas van Overeem} and Christoffersen, {Janus Wiese Holdal} and J{\"a}ger, {Anne Charlotte} and {de Wind}, Niels and Nielsen, {Finn Cilius} and {Mathiesen T{\o}rring}, Pernille and Rasmussen, {Lene Juel}",
    year = "2012",
    doi = "10.1002/humu.22153",
    language = "English",
    volume = "33",
    pages = "1647–1655",
    journal = "Human Mutation",
    issn = "1059-7794",
    publisher = "JohnWiley & Sons, Inc.",
    number = "12",

    }

    Andersen, SD, Liberti, SE, Lützen, A, Drost, M, Bernstein, I, Nilbert, M, Dominquez, M, Nyström, M, Hansen, TVO, Christoffersen, JWH, Jäger, AC, de Wind, N, Nielsen, FC, Mathiesen Tørring, P & Rasmussen, LJ 2012, 'Functional characterization of MLH1 missense variants identified in lynch syndrome patients', Human Mutation, bind 33, nr. 12, s. 1647–1655. https://doi.org/10.1002/humu.22153

    Functional characterization of MLH1 missense variants identified in lynch syndrome patients. / Andersen, Sofie Dabros; Liberti, Sascha Emilie; Lützen, Anne; Drost, Mark; Bernstein, Inge ; Nilbert, Mef ; Dominquez, Mev; Nyström, Minna ; Hansen, Thomas van Overeem; Christoffersen, Janus Wiese Holdal ; Jäger, Anne Charlotte; de Wind, Niels; Nielsen, Finn Cilius; Mathiesen Tørring, Pernille; Rasmussen, Lene Juel.

    I: Human Mutation, Bind 33, Nr. 12, 2012, s. 1647–1655.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - Functional characterization of MLH1 missense variants identified in lynch syndrome patients

    AU - Andersen, Sofie Dabros

    AU - Liberti, Sascha Emilie

    AU - Lützen, Anne

    AU - Drost, Mark

    AU - Bernstein, Inge

    AU - Nilbert, Mef

    AU - Dominquez, Mev

    AU - Nyström, Minna

    AU - Hansen, Thomas van Overeem

    AU - Christoffersen, Janus Wiese Holdal

    AU - Jäger, Anne Charlotte

    AU - de Wind, Niels

    AU - Nielsen, Finn Cilius

    AU - Mathiesen Tørring, Pernille

    AU - Rasmussen, Lene Juel

    PY - 2012

    Y1 - 2012

    N2 - Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein–protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein–protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants

    AB - Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein–protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein–protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants

    U2 - 10.1002/humu.22153

    DO - 10.1002/humu.22153

    M3 - Journal article

    VL - 33

    SP - 1647

    EP - 1655

    JO - Human Mutation

    JF - Human Mutation

    SN - 1059-7794

    IS - 12

    ER -

    Andersen SD, Liberti SE, Lützen A, Drost M, Bernstein I, Nilbert M et al. Functional characterization of MLH1 missense variants identified in lynch syndrome patients. Human Mutation. 2012;33(12):1647–1655. https://doi.org/10.1002/humu.22153