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

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

Author information

1
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany.

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.

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.

PMID:
18779421
PMCID:
PMC2742976
DOI:
10.1001/archneur.65.9.1185
[Indexed for MEDLINE]
Free PMC Article
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