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.
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-SOD1ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.
Authors: Manuela Neumann; Deepak M Sampathu; Linda K Kwong; Adam C Truax; Matthew C Micsenyi; Thomas T Chou; Jennifer Bruce; Theresa Schuck; Murray Grossman; Christopher M Clark; Leo F McCluskey; Bruce L Miller; Eliezer Masliah; Ian R Mackenzie; Howard Feldman; Wolfgang Feiden; Hans A Kretzschmar; John Q Trojanowski; Virginia M-Y Lee Journal: Science Date: 2006-10-06 Impact factor: 47.728
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