title: A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro.
abstract: TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Winton
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Wuxing
authors.initials: W
authors.lastname: Yuan
authors.forename: Elisabeth McCarty
authors.initials: EM
authors.lastname: Wood
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Richard
authors.initials: R
authors.lastname: Caselli
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D012306:Risk; D012995:Solubility
chemical_list: D004268:DNA-Binding Proteins; D019913:Nuclear Localization Signals