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      NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

      research-article
      1 , 2 , 2 , 3 , 4 , 1 , 2 , 2 , 2 , 5 , 1 , 5 , 5 , 5 , 2 , 5 , 1 , 5 , 1 , 3 , 6 , 7 , 5 , 5 , 3 , 4 , 8 , 9 , 3 , 4 , 5 , 5 , 3 , 10 , 11 , 12 , 12 , 11 , 1 , 1 , 13 , 13 , 14 , 15 , 16 , 17 , SLAGEN Consortium, 19 , 20 , 21 , 20 , 22 , 20 , 23 , 23 , 23 , 24 , 25 , 26 , 26 , 26 , 27 , 28 , 29 , 29 , 30 , 31 , 30 , 31 , 32 , 33 , 32 , 33 , 9 , 27 , 34 , 35 , 34 , 3 , 4 , 13 , 36 , 37 , 7 , 38 , 39 , 38 , 1 , 5 , 3 , 4 , 5 , 2 , 2 , 1
      Nature genetics
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

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          Author and article information

          Journal
          9216904
          2419
          Nat Genet
          Nat. Genet.
          Nature genetics
          1061-4036
          1546-1718
          23 June 2017
          25 July 2016
          September 2016
          17 August 2017
          : 48
          : 9
          : 1037-1042
          Affiliations
          [1 ]Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
          [2 ]Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands
          [3 ]Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy
          [4 ]Department of Pathophysiology and Transplantation, ‘Dino Ferrari’ Center, Università degli Studi di Milano, Milan, Italy
          [5 ]Maurice Wohl Clinical Neuroscience Institute, King’s College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK
          [6 ]Doctoral School in Molecular Medicine, Department of Sciences and Biomedical Technologies, Università degli Studi di Milano, Milan, Italy
          [7 ]Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
          [8 ]Salvatore Maugeri Foundation, IRCSS, Scientific Institute of Milano, Milan, Italy
          [9 ]‘Rita Levi Montalcini’ Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy
          [10 ]Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK
          [11 ]Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
          [12 ]Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
          [13 ]Department of Neurology, Emory University, Atlanta, Georgia, USA
          [14 ]Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, Madrid, Spain
          [15 ]Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
          [16 ]Institute of Human Genetics, Technische Universität München, Munich, Germany
          [17 ]Faculty of Medicine, University of Southampton, Southampton, UK
          [19 ]3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy
          [20 ]Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
          [21 ]Trafford Centre for Medical Research, Brighton and Sussex Medical School, Falmer, UK
          [22 ]ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia
          [23 ]Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
          [24 ]Institute of Clinical Studies, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
          [25 ]Department of Neurology, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK
          [26 ]Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
          [27 ]Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy
          [28 ]Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA
          [29 ]Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
          [30 ]Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Madrid, Spain
          [31 ]Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-723, Madrid, Spain
          [32 ]Laboratory of Neurobiology, Department of Neurosciences, KU Leuven and Vesalius Research Centre, VIB, Leuven, Belgium
          [33 ]Department of Neurology, University Hospitals, Leuven, Belgium
          [34 ]Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany
          [35 ]Department of Child and Adolescent Psychiatry, University Hospital of Würzburg, Würzburg, Germany
          [36 ]ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain
          [37 ]NDAL, Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey
          [38 ]Neurology Department, Ulm University, Ulm, Germany
          [39 ]Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
          Author notes
          Correspondence should be addressed to J.H.V. ( j.h.veldink@ 123456umcutrecht.nl )
          [18]

          A list of members and affiliations appears at the end of the paper

          SLAGEN Consortium:

          Sandra D’Alfonso 42, Letizia Mazzini 43, Giacomo P Comi 4,44, Roberto Del Bo 4,44, Mauro Ceroni 45,46, Stella Gagliardi 45, Giorgia Querin 47, Cinzia Bertolin 47, Viviana Pensato 27, Barbara Castellotti 27, Stefania Corti 4,44, Cristina Cereda 45, Lucia Corrado 42 & Gianni Sorarù 47

          42Department of Health Sciences, University of Eastern Piedmont, Novara, Italy. 43ALS Center, Department of Neurology, ‘A. Avogadro’ University of Eastern Piedmont, Novara, Italy. 44Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. 45Experimental Neurobiology Laboratory, ‘C. Mondino’ National Institute of Neurology Foundation, IRCCS, Pavia, Italy. 46Department of Neurological Sciences, University of Pavia, Pavia, Italy. 47Department of Neurosciences, University of Padova, Padova, Italy.

          [40]

          These authors contributed equally to this work

          [41]

          These authors jointly directed this work

          Article
          PMC5560030 PMC5560030 5560030 nihpa885013
          10.1038/ng.3626
          5560030
          27455347
          9588600f-33ba-4be4-be90-fc6f99f9a1e3

          Reprints and permissions information is available online at http://www.nature.com/reprints/index.html.

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