TARDBP and FUS Mutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

Authors

  • Serena Lattante,

    1. Institut du Cerveau et de la Moelle épinière, Centre de Recherche, CHU Pitié-Salpétrière, Inserm, UMR_S975, CRICM, F-75013; UPMC Univ Paris 06, UMR_S975, F-75013; CNRS UMR 7225, Paris, France
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  • Guy A. Rouleau,

    1. Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
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  • Edor Kabashi

    Corresponding author
    1. Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
    • Institut du Cerveau et de la Moelle épinière, Centre de Recherche, CHU Pitié-Salpétrière, Inserm, UMR_S975, CRICM, F-75013; UPMC Univ Paris 06, UMR_S975, F-75013; CNRS UMR 7225, Paris, France
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  • Communicated by Mireille Clustres

Correspondence to: Edor Kabashi, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie-Paris, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France. E-mail: edor.kabashi@icm-institute.org

ABSTRACT

Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.

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