2. Academic Validation
  3. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

  • Nat Commun. 2016 Apr 15;7:11253. doi: 10.1038/ncomms11253.
Kelly L Williams 1 2 3,  Simon Topp 4,  Shu Yang 1 2,  Bradley Smith 4,  Jennifer A Fifita 1 2,  Sadaf T Warraich 1,  Katharine Y Zhang 1,  Natalie Farrawell 5,  Caroline Vance 4,  Xun Hu 4,  Alessandra Chesi 6,  Claire S Leblond 7 8,  Albert Lee 1 9,  Stephanie L Rayner 1,  Vinod Sundaramoorthy 1 10,  Carol Dobson-Stone 11 12,  Mark P Molloy 1 9,  Marka van Blitterswijk 13,  Dennis W Dickson 13,  Ronald C Petersen 14,  Neill R Graff-Radford 15,  Bradley F Boeve 14,  Melissa E Murray 13,  Cyril Pottier 13,  Emily Don 1,  Claire Winnick 1,  Emily P McCann 1,  Alison Hogan 1,  Hussein Daoud 7 8,  Annie Levert 7 8,  Patrick A Dion 7 8,  Jun Mitsui 16,  Hiroyuki Ishiura 16,  Yuji Takahashi 16,  Jun Goto 16,  Jason Kost 17 18,  Cinzia Gellera 19,  Athina Soragia Gkazi 4,  Jack Miller 4,  Joanne Stockton 20,  William S Brooks 11,  Karyn Boundy 21,  Meraida Polak 22,  José Luis Muñoz-Blanco 23,  Jesús Esteban-Pérez 24 25,  Alberto Rábano 26,  Orla Hardiman 27,  Karen E Morrison 20 28 29,  Nicola Ticozzi 30 31,  Vincenzo Silani 30 31,  Jacqueline de Belleroche 32,  Jonathan D Glass 22,  John B J Kwok 11 12,  Gilles J Guillemin 1,  Roger S Chung 1,  Shoji Tsuji 16 33,  Robert H Brown Jr 18,  Alberto García-Redondo 24 25,  Rosa Rademakers 13,  John E Landers 18,  Aaron D Gitler 6,  Guy A Rouleau 7 8,  Nicholas J Cole 1 3,  Justin J Yerbury 5,  Julie D Atkin 1 10,  Christopher E Shaw 4,  Garth A Nicholson 1 2 3 34,  Ian P Blair 1 2
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
  • 2 Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
  • 3 Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
  • 4 Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
  • 5 Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • 6 Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
  • 7 Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.
  • 8 Pathology and Cellular Biology Department, Montreal University, Montreal, QC H3T 1J4 Québec, Canada.
  • 9 Australian Proteome Analysis Facility, Macquarie University, Sydney, New South Wales 2109, Australia.
  • 10 Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia.
  • 11 Neuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.
  • 12 School of Medical Sciences, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia.
  • 13 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
  • 14 Department of Neurology, Mayo Clinic Rochester, Rochester, Minneapolis 55905, USA.
  • 15 Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, 32224, USA.
  • 16 Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
  • 17 Worcester Polytechnic Institute, Worcester, Massachusetts 01609, USA.
  • 18 Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • 19 Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
  • 20 School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 21 The Queen Elizabeth Hospital, Woodville South, South Australia 5011, Australia.
  • 22 Department of Neurology, Emory University, Atlanta, Georgia 30322, USA.
  • 23 Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, Sermas 28007, Spain.
  • 24 Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Sermas 28041, Spain.
  • 25 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid 28029, Spain.
  • 26 Banco de Tejidos, Centro Alzheimer-Fundación Reina Sofia, Fundación CIEN, Madrid 28071, Spain.
  • 27 Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
  • 28 Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK.
  • 29 Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
  • 30 Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
  • 31 Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, 20122 Milan, Italy.
  • 32 Neurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
  • 33 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
  • 34 Molecular Medicine Laboratory, Concord Hospital, New South Wales 2139, Australia.
PMID: 27080313 DOI: 10.1038/ncomms11253
Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

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