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Two German Kindreds With Familial Amyotrophic Lateral Sclerosis Due to TARDBP Mutations.
Kuhnlein, Peter MD; Sperfeld, Anne-Dorte MD; Vanmassenhove, Ben MTA; Van Deerlin, Vivianna MD, PhD; Lee, Virginia M.-Y. PhD; Trojanowski, John Q. MD, PhD; Kretzschmar, Hans A. MD; Ludolph, Albert C. MD; Neumann, Manuela MD
[Article] Archives of Neurology. 65(9):1185-1189, September 2008.

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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.