CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Kelly L. Williams, Simon Topp, Shu Yang, Bradley Smith, Jennifer A. Fifita, Sadaf T. Warraich, Katharine Y. Zhang, Natalie Farrawell, Caroline Vance, Xun Hu, Alessandra Chesi, Claire S. Leblond, Albert Lee, Stephanie L. Rayner, Vinod Sundaramoorthy, Carol Dobson-Stone, Mark P. Molloy, Marka van Blitterswijk, Dennis W. Dickson, Ronald C. Petersen, Neill R. Graff-Radford, Bradley F. Boeve, Melissa E. Murray, Cyril Pottier, Emily Don, Claire Winnick, Emily P. McCann, Alison Hogan, Hussein Daoud, Annie Levert, Patrick A. Dion, Jun Mitsui, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Jason Kost, Cinzia Gellera, Athina Soragia Gkazi, Jack Miller, Joanne Stockton, William S. Brooks, Karyn Boundy, Meraida Polak, José Luis Muñoz-Blanco, Jesús Esteban-Pérez, Alberto Rábano, Orla Hardiman, Karen E. Morrison, Nicola Ticozzi, Vincenzo Silani, Jacqueline de Belleroche, Jonathan D. Glass, John B. J. Kwok, Gilles J. Guillemin, Roger S. Chung, Shoji Tsuji, Robert H. Brown, Alberto García-Redondo, Rosa Rademakers, John E. Landers, Aaron D. Gitler, Guy A. Rouleau, Nicholas J. Cole, Justin J. Yerbury, Julie D. Atkin, Christopher E. Shaw, Garth A. Nicholson and Ian P. Blair ()
Additional contact information
Kelly L. Williams: Faculty of Medicine and Health Sciences, Macquarie University
Simon Topp: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Shu Yang: Faculty of Medicine and Health Sciences, Macquarie University
Bradley Smith: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Jennifer A. Fifita: Faculty of Medicine and Health Sciences, Macquarie University
Sadaf T. Warraich: Faculty of Medicine and Health Sciences, Macquarie University
Katharine Y. Zhang: Faculty of Medicine and Health Sciences, Macquarie University
Natalie Farrawell: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong
Caroline Vance: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Xun Hu: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Alessandra Chesi: Stanford University School of Medicine
Claire S. Leblond: Montreal Neurological Institute and Hospital, McGill University
Albert Lee: Faculty of Medicine and Health Sciences, Macquarie University
Stephanie L. Rayner: Faculty of Medicine and Health Sciences, Macquarie University
Vinod Sundaramoorthy: Faculty of Medicine and Health Sciences, Macquarie University
Carol Dobson-Stone: Neuroscience Research Australia, Randwick
Mark P. Molloy: Faculty of Medicine and Health Sciences, Macquarie University
Marka van Blitterswijk: Mayo Clinic Florida
Dennis W. Dickson: Mayo Clinic Florida
Ronald C. Petersen: Mayo Clinic Rochester
Neill R. Graff-Radford: Mayo Clinic Florida
Bradley F. Boeve: Mayo Clinic Rochester
Melissa E. Murray: Mayo Clinic Florida
Cyril Pottier: Mayo Clinic Florida
Emily Don: Faculty of Medicine and Health Sciences, Macquarie University
Claire Winnick: Faculty of Medicine and Health Sciences, Macquarie University
Emily P. McCann: Faculty of Medicine and Health Sciences, Macquarie University
Alison Hogan: Faculty of Medicine and Health Sciences, Macquarie University
Hussein Daoud: Montreal Neurological Institute and Hospital, McGill University
Annie Levert: Montreal Neurological Institute and Hospital, McGill University
Patrick A. Dion: Montreal Neurological Institute and Hospital, McGill University
Jun Mitsui: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo
Hiroyuki Ishiura: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo
Yuji Takahashi: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo
Jun Goto: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo
Jason Kost: Worcester Polytechnic Institute
Cinzia Gellera: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’
Athina Soragia Gkazi: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Jack Miller: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Joanne Stockton: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham
William S. Brooks: Neuroscience Research Australia, Randwick
Karyn Boundy: The Queen Elizabeth Hospital
Meraida Polak: Emory University
José Luis Muñoz-Blanco: Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid
Jesús Esteban-Pérez: Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid
Alberto Rábano: Banco de Tejidos, Centro Alzheimer—Fundación Reina Sofia, Fundación CIEN
Orla Hardiman: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Karen E. Morrison: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham
Nicola Ticozzi: IRCCS Istituto Auxologico Italiano
Vincenzo Silani: IRCCS Istituto Auxologico Italiano
Jacqueline de Belleroche: Neurogenetics Group, Imperial College London, Hammersmith Hospital Campus
Jonathan D. Glass: Emory University
John B. J. Kwok: Neuroscience Research Australia, Randwick
Gilles J. Guillemin: Faculty of Medicine and Health Sciences, Macquarie University
Roger S. Chung: Faculty of Medicine and Health Sciences, Macquarie University
Shoji Tsuji: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo
Robert H. Brown: University of Massachusetts Medical School
Alberto García-Redondo: Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid
Rosa Rademakers: Mayo Clinic Florida
John E. Landers: University of Massachusetts Medical School
Aaron D. Gitler: Stanford University School of Medicine
Guy A. Rouleau: Montreal Neurological Institute and Hospital, McGill University
Nicholas J. Cole: Faculty of Medicine and Health Sciences, Macquarie University
Justin J. Yerbury: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong
Julie D. Atkin: Faculty of Medicine and Health Sciences, Macquarie University
Christopher E. Shaw: Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London
Garth A. Nicholson: Faculty of Medicine and Health Sciences, Macquarie University
Ian P. Blair: Faculty of Medicine and Health Sciences, Macquarie University

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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 (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

Date: 2016
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DOI: 10.1038/ncomms11253

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