Review Article | Published:

State of play in amyotrophic lateral sclerosis genetics

Nature Neuroscience volume 17, pages 1723 (2014) | Download Citation

Abstract

Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.

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Acknowledgements

This work was supported in part by the Intramural Research Programs of the US National Institutes of Health, National Institute on Aging (Z01-AG000949-02) and National Institute of Neurological Disorders and Stroke. The work was also supported by the Packard Center for ALS Research at Hopkins (B.J.T.), the ALS Association (B.J.T., A.C.), Microsoft Research (B.J.T.), AriSLA (B.J.T., A.C.), the Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007 to A.C.), Fondazione Vialli e Mauro ONLUS (A.C.), Federazione Italiana Giuoco Calcio (A.C., B.J.T.), Compagnia di San Paolo (A.C.) and the European Community's Health Seventh Framework Programme under grant agreement 259867 (A.C.).

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Affiliations

  1. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Alan E Renton
    •  & Bryan J Traynor
  2. Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.

    • Adriano Chiò
  3. Department of Neurology, Brain Sciences Institute, Johns Hopkins University, Baltimore, Maryland, USA.

    • Bryan J Traynor

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Competing interests

B.J.T. has a patent pending on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9ORF72.

Corresponding author

Correspondence to Bryan J Traynor.

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https://doi.org/10.1038/nn.3584