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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.
Kenna, Kevin P; van Doormaal, Perry T C; Dekker, Annelot M; Ticozzi, Nicola; Kenna, Brendan J; Diekstra, Frank P; van Rheenen, Wouter; van Eijk, Kristel R; Jones, Ashley R; Keagle, Pamela; Shatunov, Aleksey; Sproviero, William; Smith, Bradley N; van Es, Michael A; Topp, Simon D; Kenna, Aoife; Miller, Jack W; Fallini, Claudia; Tiloca, Cinzia; McLaughlin, Russell L; Vance, Caroline; Troakes, Claire; Colombrita, Claudia; Mora, Gabriele; Calvo, Andrea; Verde, Federico; Al-Sarraj, Safa; King, Andrew; Calini, Daniela; de Belleroche, Jacqueline; Baas, Frank; van der Kooi, Anneke J; de Visser, Marianne; Ten Asbroek, Anneloor L M A; Sapp, Peter C; McKenna-Yasek, Diane; Polak, Meraida; Asress, Seneshaw; Muñoz-Blanco, José Luis; Strom, Tim M; Meitinger, Thomas; Morrison, Karen E; Lauria, Giuseppe; Williams, Kelly L; Leigh, P Nigel; Nicholson, Garth A; Blair, Ian P; Leblond, Claire S; Dion, Patrick A; Rouleau, Guy A.
Affiliation
  • Kenna KP; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • van Doormaal PT; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Dekker AM; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Ticozzi N; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  • Kenna BJ; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
  • Diekstra FP; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • van Rheenen W; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • van Eijk KR; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Jones AR; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Keagle P; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Shatunov A; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • Sproviero W; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Smith BN; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • van Es MA; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Topp SD; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Kenna A; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Miller JW; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • Fallini C; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Tiloca C; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • McLaughlin RL; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  • Vance C; Doctoral School in Molecular Medicine, Department of Sciences and Biomedical Technologies, Università degli Studi di Milano, Milan, Italy.
  • Troakes C; Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
  • Colombrita C; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Mora G; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • Calvo A; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  • Verde F; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
  • Al-Sarraj S; Salvatore Maugeri Foundation, IRCSS, Scientific Institute of Milano, Milan, Italy.
  • King A; 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
  • Calini D; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  • de Belleroche J; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
  • Baas F; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • van der Kooi AJ; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
  • de Visser M; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
  • Ten Asbroek AL; Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.
  • Sapp PC; Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
  • McKenna-Yasek D; Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
  • Polak M; Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
  • Asress S; Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
  • Muñoz-Blanco JL; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • Strom TM; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • Meitinger T; Department of Neurology, Emory University, Atlanta, Georgia, USA.
  • Morrison KE; Department of Neurology, Emory University, Atlanta, Georgia, USA.
  • Lauria G; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • Williams KL; Institute of Human Genetics, Technische Universität München, Munich, Germany.
  • Leigh PN; Faculty of Medicine, University of Southampton, Southampton, UK.
  • Blair IP; 3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
  • Leblond CS; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
  • Dion PA; Trafford Centre for Medical Research, Brighton and Sussex Medical School, Falmer, UK.
  • Rouleau GA; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Nat Genet ; 48(9): 1037-42, 2016 09.
Article de En | MEDLINE | ID: mdl-27455347
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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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Prédisposition génétique à une maladie / Kinase-1 apparentée à NIMA / Sclérose latérale amyotrophique / Mutation Type d'étude: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limites: Humans Pays/Région comme sujet: Europa Langue: En Journal: Nat Genet Sujet du journal: GENETICA MEDICA Année: 2016 Type de document: Article Pays d'affiliation: États-Unis d'Amérique
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Prédisposition génétique à une maladie / Kinase-1 apparentée à NIMA / Sclérose latérale amyotrophique / Mutation Type d'étude: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limites: Humans Pays/Région comme sujet: Europa Langue: En Journal: Nat Genet Sujet du journal: GENETICA MEDICA Année: 2016 Type de document: Article Pays d'affiliation: États-Unis d'Amérique