NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

Szczegóły
Abstrakt

Tytuł:: NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.
Autorzy:: 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.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Kenna BJ; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Diekstra FP; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
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; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Keagle P; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Shatunov A; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
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; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
Topp SD; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Kenna A; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Miller JW; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Fallini C; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Tiloca C; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Doctoral School in Molecular Medicine, Department of Sciences and Biomedical Technologies, Università degli Studi di Milano, Milan, Italy.
McLaughlin RL; Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Vance C; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Troakes C; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Colombrita C; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Mora G; Salvatore Maugeri Foundation, IRCSS, Scientific Institute of Milano, Milan, Italy.
Calvo A; 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Verde F; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Al-Sarraj S; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
King A; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Calini D; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.
de Belleroche J; Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.
Baas F; Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
van der Kooi AJ; Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
de Visser M; Department of Neurogenetics and Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Ten Asbroek AL; Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Sapp PC; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
McKenna-Yasek D; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Polak M; Department of Neurology, Emory University, Atlanta, Georgia, USA.
Asress S; Department of Neurology, Emory University, Atlanta, Georgia, USA.
Muñoz-Blanco JL; Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, Madrid, Spain.
Strom TM; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Meitinger T; Institute of Human Genetics, Technische Universität München, Munich, Germany.
Morrison KE; Faculty of Medicine, University of Southampton, Southampton, UK.
Lauria G; 3rd Neurology Unit, Motor Neuron Diseases Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Williams KL; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Leigh PN; Trafford Centre for Medical Research, Brighton and Sussex Medical School, Falmer, UK.
Nicholson GA; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.; ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia.
Blair IP; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Leblond CS; Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Dion PA; Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Rouleau GA; Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Pall H; Institute of Clinical Studies, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.; Department of Neurology, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK.
Shaw PJ; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Turner MR; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Talbot K; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Taroni F; Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Boylan KB; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
Van Blitterswijk M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Rademakers R; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Esteban-Pérez J; Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-723, Madrid, Spain.
García-Redondo A; Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-723, Madrid, Spain.
Van Damme P; Laboratory of Neurobiology, Department of Neurosciences, KU Leuven and Vesalius Research Centre, VIB, Leuven, Belgium.; Department of Neurology, University Hospitals, Leuven, Belgium.
Robberecht W; Laboratory of Neurobiology, Department of Neurosciences, KU Leuven and Vesalius Research Centre, VIB, Leuven, Belgium.; Department of Neurology, University Hospitals, Leuven, Belgium.
Chio A; 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
Gellera C; Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Drepper C; Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.; Department of Child and Adolescent Psychiatry, University Hospital of Würzburg, Würzburg, Germany.
Sendtner M; Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany.
Ratti A; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Glass JD; Department of Neurology, Emory University, Atlanta, Georgia, USA.
Mora JS; ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain.
Basak NA; NDAL, Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
Hardiman O; Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Ludolph AC; Neurology Department, Ulm University, Ulm, Germany.
Andersen PM; Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Weishaupt JH; Neurology Department, Ulm University, Ulm, Germany.
Brown RH Jr; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Al-Chalabi A; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Silani V; Department of Neurology, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Shaw CE; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
van den Berg LH; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
Veldink JH; Department of Neurology Brain Centre, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands.
Landers JE; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Corporate Authors:: SLAGEN Consortium
Źródło:: Nature genetics [Nat Genet] 2016 Sep; Vol. 48 (9), pp. 1037-42. Date of Electronic Publication: 2016 Jul 25.
Typ publikacji:: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: New York, NY : Nature Pub. Co., c1992-
MeSH Terms:: Genetic Predisposition to Disease*
Amyotrophic Lateral Sclerosis/*genetics
Mutation/*genetics
NIMA-Related Kinase 1/*genetics
Amyotrophic Lateral Sclerosis/epidemiology ; Case-Control Studies ; Cohort Studies ; Exome/genetics ; Genetic Association Studies ; Humans ; Netherlands/epidemiology
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Grant Information:: HHSN268201100009I United States HL NHLBI NIH HHS; MR/L501529/1 United Kingdom MRC_ Medical Research Council; U01 AG032984 United States AG NIA NIH HHS; HHSN268201100007C United States HL NHLBI NIH HHS; HHSN268201100011I United States HL NHLBI NIH HHS; U54 HG003079 United States HG NHGRI NIH HHS; MC_G1000733 United Kingdom MRC_ Medical Research Council; G0900688 United Kingdom MRC_ Medical Research Council; U01 AG049505 United States AG NIA NIH HHS; HHSN268201100012C United States HL NHLBI NIH HHS; RC2 HL102419 United States HL NHLBI NIH HHS; U54 HG003067 United States HG NHGRI NIH HHS; HHSN268201100010C United States HL NHLBI NIH HHS; U24 AG021886 United States AG NIA NIH HHS; HHSN268201100008C United States HL NHLBI NIH HHS; HHSN268201100005G United States HL NHLBI NIH HHS; U01 AG049507 United States AG NIA NIH HHS; HHSN268201100008I United States HL NHLBI NIH HHS; United States HHMI Howard Hughes Medical Institute; SMITH/APR16/847-791 United Kingdom MNDA_ Motor Neurone Disease Association; HHSN268201100011C United States HL NHLBI NIH HHS; U01 AG016976 United States AG NIA NIH HHS; MRF_MRF-060-0003-RG-SMITH United Kingdom MRF MRF; UF1 AG047133 United States AG NIA NIH HHS; U54 HG003273 United States HG NHGRI NIH HHS; R01 NS073873 United States NS NINDS NIH HHS; R01 HL105756 United States HL NHLBI NIH HHS; HHSN268201100006C United States HL NHLBI NIH HHS; U24 AG041689 United States AG NIA NIH HHS; R01 AG033193 United States AG NIA NIH HHS; JONES/OCT15/958-799 United Kingdom MNDA_ Motor Neurone Disease Association; HHSN268201100005I United States HL NHLBI NIH HHS; TURNER/JAN13/944-795 United Kingdom MNDA_ Motor Neurone Disease Association; G0600974 United Kingdom MRC_ Medical Research Council; U01 AG049508 United States AG NIA NIH HHS; MR/K01014X/1 United Kingdom MRC_ Medical Research Council; MR/K000039/1 United Kingdom MRC_ Medical Research Council; HHSN268201100009C United States HL NHLBI NIH HHS; HHSN268201100005C United States HL NHLBI NIH HHS; HHSN268201100007I United States HL NHLBI NIH HHS; U01 AG049506 United States AG NIA NIH HHS; United Kingdom WT_ Wellcome Trust
Contributed Indexing:: Investigator: S D'Alfonso; L Mazzini; GP Comi; R Del Bo; M Ceroni; S Gagliardi; G Querin; C Bertolin; V Pensato; B Castellotti; S Corti; C Cereda; L Corrado; G Sorarù
Substance Nomenclature:: EC 2.7.11.1 (NEK1 protein, human)
EC 2.7.11.1 (NIMA-Related Kinase 1)
Entry Date(s):: Date Created: 20160726 Date Completed: 20170907 Latest Revision: 20240320
Update Code:: 20240320
PubMed Central ID:: PMC5560030
DOI:: 10.1038/ng.3626
PMID:: 27455347
: Czasopismo naukowe

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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