title: Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.
abstract: BACKGROUND
  Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS.
  
  
  OBJECTIVE
  To investigate the presence and frequency of TARDBP mutations in ALS.
  
  
  METHODS
  Genetic analysis.
  
  
  METHODS
  Academic research.
  
  
  METHODS
  One hundred thirty-four patients with sporadic ALS, 31 patients with familial non-superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects.
  
  
  METHODS
  We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment.
  
  
  RESULTS
  The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges.
  
  
  CONCLUSIONS
  Mutations in TARDBP are a rare cause of familial non-SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kühnlein
authors.forename: Anne-Dorte
authors.initials: AD
authors.lastname: Sperfeld
authors.forename: Ben
authors.initials: B
authors.lastname: Vanmassenhove
authors.forename: Vivianna
authors.initials: V
authors.lastname: Van Deerlin
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree
chemical_list: D004268:DNA-Binding Proteins
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