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Peter Kühnlein, MD; Anne-Dorte Sperfeld, MD; Ben Vanmassenhove, MTA; Vivianna Van Deerlin, MD, PhD; Virginia M.-Y. Lee, PhD; John Q. Trojanowski, MD, PhD; Hans A. Kretzschmar, MD; Albert C. Ludolph, MD; Manuela Neumann, MD

Arch Neurol. 2008;65(9):1185-1189.

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.

Author Affiliations: Department of Neurology, University of Ulm, Ulm (Drs Kühnlein, Sperfeld, and Ludolph), and Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich (Mr Vanmassenhove and Drs Kretzschmar and Neumann), Germany; and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine (Drs Van Deerlin, Lee, and Trojanowski), University of Pennsylvania School of Medicine, Philadelphia.

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