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Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

PLoS genetics | Sep 19, 2008

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

Pubmed ID: 18802454 RIS Download

Mesh terms: Adult | Aged | Aged, 80 and over | Alleles | Amyotrophic Lateral Sclerosis | Cell Line, Tumor | Cohort Studies | DNA Mutational Analysis | DNA-Binding Proteins | Female | Humans | Male | Middle Aged | Mutation, Missense | Neurodegenerative Diseases | Pedigree

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Associated grants

  • Agency: NIA NIH HHS, Id: P30 AG013854
  • Agency: NIA NIH HHS, Id: P50 AG16574
  • Agency: NINDS NIH HHS, Id: R01 NS42759-04S1
  • Agency: NINDS NIH HHS, Id: P50 NS040256
  • Agency: NIA NIH HHS, Id: P30 AG13854
  • Agency: NIA NIH HHS, Id: P50 AG016574
  • Agency: NINDS NIH HHS, Id: P50 NS 40256
  • Agency: NIA NIH HHS, Id: P30 AG013854-139003
  • Agency: NIA NIH HHS, Id: P01 AG17216
  • Agency: NIA NIH HHS, Id: R01 AG015866
  • Agency: NINDS NIH HHS, Id: P01 NS040256
  • Agency: NIA NIH HHS, Id: P01 AG03949
  • Agency: Medical Research Council, Id: G0500289
  • Agency: NINDS NIH HHS, Id: R01 NS42759
  • Agency: NIA NIH HHS, Id: U01 AG06786
  • Agency: NIA NIH HHS, Id: P50 AG25711
  • Agency: NINDS NIH HHS, Id: NS40256
  • Agency: NIA NIH HHS, Id: AG19610-01
  • Agency: NIA NIH HHS, Id: P01 AG003949
  • Agency: NIA NIH HHS, Id: P30 AG019610
  • Agency: NIA NIH HHS, Id: R01 AG026251
  • Agency: NIA NIH HHS, Id: P50 AG025711
  • Agency: NIA NIH HHS, Id: P01 AG017216
  • Agency: NIA NIH HHS, Id: R01 AG026251-01
  • Agency: NIA NIH HHS, Id: U01 AG006786
  • Agency: NINDS NIH HHS, Id: R01 NS042759

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