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TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis


Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals—six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)—and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.

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Figure 1: TARDBP mutations in individuals with ALS and their effect on the translated protein.


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We would like to thank all the families involved in this study. We also thank M. Benard, I. Thibault and P. Provencher for sample collection and organization, M. D'Amour and D. Brunet for providing access to their patients and A. Dyck and J. St-Onge for technical support. G.A.R. is funded by the Canadian Institutes of Health Research (CIHR), Muscular Dystrophy Association USA and ALS Association (ALSA), E.K. by ALS Canada and CIHR, N.D. by CIHR, P.N.V. by the Fonds de Recherche en Sante Quebec (FRSQ) and V.M. by the Association Francaise contre les Myopathies France (AMF) and the Association pour la Recherche sur la Sclerose Laterale Amyotrophique (ARS).

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Authors and Affiliations



E.K. and P.N.V. generated the data, conducted the data analysis, wrote the manuscript and led the project; P.D. participated in the data analysis and review of the manuscript; E.K. and P.D. conducted the functional analysis of lymphoblastoid cell lines derived from individuals with ALS; P.N.V. conducted haplotype and performed 3D modelling; D.S. performed sequence and data analysis; B.J.M. conducted bioinformatic analysis of mutations and reviewed the manuscript; C.V.V. performed functional analysis and reviewed the manuscript. J.-P.B., L.L., K.P., F.S., P.-F.P., W.C., V.M. and N.D. conducted neurological evaluation and family history of individuals with ALS and reviewed the manuscript. G.A.R. conducted neurological evaluation of individuals with ALS, participated in the data analysis, reviewed the manuscript and supervised the project.

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Correspondence to Guy A Rouleau.

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Supplementary Tables 1–4, Supplementary Figures 1 and 2, Supplementary Note and Supplementary Methods (PDF 239 kb)

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Kabashi, E., Valdmanis, P., Dion, P. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40, 572–574 (2008).

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