Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Aude Nicolas, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA.
Kevin P. Kenna, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Alan E. Renton, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nicola Ticozzi, Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center - Università degli Studi di Milano, Milan 20122, Italy.
Faraz Faghri, Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA; Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Ruth Chia, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA.
Janice A. Dominov, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Brendan J. Kenna, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mike A. Nalls, Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD, USA.
Pamela Keagle, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Alberto M. Rivera, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA.
Wouter van Rheenen, Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Natalie A. Murphy, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA.
Joke J. van Vugt, Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Joshua T. Geiger, Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
Rick A. Van der Spek, Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Hannah A. Pliner, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA.
Shankaracharya, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Bradley N. Smith, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London SE5 9RS, UK.
Giuseppe Marangi, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA; Institute of Genomic Medicine, Catholic University, Roma, Italy.
Simon D. Topp, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London SE5 9RS, UK.
Yevgeniya Abramzon, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD 20892, USA; Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, UK.
Athina Soragia Gkazi, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London SE5 9RS, UK.
John D. Eicher, Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA 02115, USA.
Aoife Kenna, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Publication Title

Neuron

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