Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations

Arch Neurol. 2008 Sep;65(9):1185-9. doi: 10.1001/archneur.65.9.1185.


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.

Objectives: To investigate the presence and frequency of TARDBP mutations in ALS.

Design: Genetic analysis.

Setting: Academic research.

Participants: 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.

Main outcome measures: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • DNA-Binding Proteins / genetics*
  • Female
  • Germany
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Pedigree


  • DNA-Binding Proteins