title: Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome.
abstract: So far 18 MLH3 germline mutations/variants have been identified in familial colorectal cancer cases. Sixteen of these variants are amino acid substitutions of which the pathogenic nature is still unclear. These substitutions are known as unclassified variants or UVs. To clarify a possible role for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary colorectal cancer, including Lynch syndrome.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Ou
authors.forename: Merete
authors.initials: M
authors.lastname: Rasmussen
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
authors.forename: Sofie D
authors.initials: SD
authors.lastname: Andersen
authors.forename: Paul O
authors.initials: PO
authors.lastname: Jager
authors.forename: Krista A
authors.initials: KA
authors.lastname: Kooi
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Lene J
authors.initials: LJ
authors.lastname: Rasmussen
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D006801:Humans; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; C403623:MLH3 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins