title: Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment.
abstract: Nearly one-third of the identified MSH6 germline mutations deal with single amino acid substitutions. For an effective genetic counselling it is necessary to clearly elucidate by functional tools the specific sub-processes underlying the mismatch repair (MMR) misfunctioning in MSH6 non-truncating mutants. Since the MMR repair pathway occurs in the nucleus, we suppose the impairment of MutSα nuclear trafficking to be a possible Lynch syndrome susceptibility causative mechanism. In the present study the MMR status of the tumour, the main clinical features of mutation carriers and population data associated to the MSH6 missense variants, were complemented with computational data about tolerability predictions and amino acid substitution conservation. The selected panel of ten potentially pathogenic MSH6 mutations was analyzed in a homologous expression system for possible deleterious effects on nucleo-cytoplasmic shuttling through the assessment of the sub-cellular localization of the corresponding mutated proteins. Localization analysis results do not reveal an apparent role of MSH6 missense mutations in nuclear import impairment and provide the first hint to exclude the MSH6 nuclear translocation sub-process as a possible causative mechanisms of MMR misfunctioning.
authors.forename: Laura
authors.initials: L
authors.lastname: Belvederesi
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.forename: Cristian
authors.initials: C
authors.lastname: Loretelli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bracci
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cellerino
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D011379:Prognosis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins