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Two German Kindreds With Familial Amyotrophic Lateral Sclerosis Due to TARDBP Mutations
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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