title: The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons.
abstract: Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30% of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem.
authors.affiliation: Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Iovino
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfisterer
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Swingler
authors.forename: Laura
authors.initials: L
authors.lastname: Calo
authors.forename: Rebecca
authors.initials: R
authors.lastname: Treacy
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Malin
authors.initials: M
authors.lastname: Parmar
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.forename: Miratul M K
authors.initials: MM
authors.lastname: Muqit
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
mesh_terms: D000368:Aged; D001344:Autopsy; D001706:Biopsy; D001921:Brain / Q000473:pathology*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D024801:Tauopathies / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins