title: TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.
abstract: BACKGROUND
  TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
  
  
  METHODS
  TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
  
  
  RESULTS
  We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available.
  
  
  CONCLUSIONS
  The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
  
  
  BACKGROUND
  National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bekris
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Wuxing
authors.initials: W
authors.lastname: Yuan
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Elman
authors.forename: Dana
authors.initials: D
authors.lastname: Clay
authors.forename: Elisabeth McCarty
authors.initials: EM
authors.lastname: Wood
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.forename: Ellen
authors.initials: E
authors.lastname: Steinbart
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: I-Lin
authors.initials: IL
authors.lastname: Wu
authors.forename: Wei-Shiung
authors.initials: WS
authors.lastname: Yang
authors.forename: Robert
authors.initials: R
authors.lastname: Kalb
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D003704:Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005192:Family Health; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012694:Serine / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D025801:Ubiquitin; D012694:Serine; D000409:Alanine; D005998:Glycine