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.
authors: Department of Science, Systems, and Models, Roskilde University, Roskilde, Denmark.
authors: Sofie Dabros
authors: SD
authors: Andersen
authors: Sascha Emilie
authors: SE
authors: Liberti
authors: Anne
authors: A
authors: Lützen
authors: Mark
authors: M
authors: Drost
authors: Inge
authors: I
authors: Bernstein
authors: Mef
authors: M
authors: Nilbert
authors: Mev
authors: M
authors: Dominguez
authors: Minna
authors: M
authors: Nyström
authors: Thomas Van Overeem
authors: TV
authors: Hansen
authors: Janus Wiese
authors: JW
authors: Christoffersen
authors: Anne Charlotte
authors: AC
authors: Jäger
authors: Niels
authors: N
authors: de Wind
authors: Finn Cilius
authors: FC
authors: Nielsen
authors: Pernille M
authors: PM
authors: Tørring
authors: Lene Juel
authors: LJ
authors: Rasmussen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D000070976:Mismatch Repair Endonuclease PMS2; D008958:Models, Molecular; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D040681:Structural Homology, Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C501486:MLH1 protein, human; C074770:MutL protein, E coli; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes