Functional characterization of MLH1 missaense variants identified in lynch syndrome patients

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

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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. Hum Mutat 33:1647-1655, 2012. © 2012 Wiley Periodicals, Inc.
TidsskriftHuman Mutation
Udgave nummer12
Sider (fra-til)1647-55
Antal sider9
StatusUdgivet - 2012

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