title: CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.
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.
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Kelly L
authors.identifier: http://orcid.org/0000-0001-6319-9473
authors.initials: KL
authors.lastname: Williams
authors.affiliation: Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Simon
authors.identifier: http://orcid.org/0000-0002-5200-3284
authors.initials: S
authors.lastname: Topp
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Fifita
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Sadaf T
authors.initials: ST
authors.lastname: Warraich
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Katharine Y
authors.initials: KY
authors.lastname: Zhang
authors.affiliation: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Farrawell
authors.affiliation: Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.affiliation: Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.affiliation: Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.|Pathology and Cellular Biology Department, Montreal University, Montreal, QC H3T 1J4 Québec, Canada.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Australian Proteome Analysis Facility, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Albert
authors.identifier: http://orcid.org/0000-0001-5156-0567
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Rayner
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Sundaramoorthy
authors.affiliation: Neuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.|School of Medical Sciences, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Dobson-Stone
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Australian Proteome Analysis Facility, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Molloy
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
authors.forename: Dennis W
authors.identifier: http://orcid.org/0000-0001-7189-7917
authors.initials: DW
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authors.affiliation: Department of Neurology, Mayo Clinic Rochester, Rochester, Minneapolis 55905, USA.
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authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, 32224, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, Rochester, Minneapolis 55905, USA.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
authors.forename: Melissa E
authors.identifier: http://orcid.org/0000-0001-7379-2545
authors.initials: ME
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authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
authors.forename: Cyril
authors.initials: C
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
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authors.initials: E
authors.lastname: Don
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Claire
authors.initials: C
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Emily P
authors.initials: EP
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
authors.forename: Alison
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authors.affiliation: Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.|Pathology and Cellular Biology Department, Montreal University, Montreal, QC H3T 1J4 Québec, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.affiliation: Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.|Pathology and Cellular Biology Department, Montreal University, Montreal, QC H3T 1J4 Québec, Canada.
authors.forename: Annie
authors.initials: A
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authors.affiliation: Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.|Pathology and Cellular Biology Department, Montreal University, Montreal, QC H3T 1J4 Québec, Canada.
authors.forename: Patrick A
authors.initials: PA
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authors.affiliation: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
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authors.affiliation: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
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authors.initials: Y
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authors.affiliation: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
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authors.affiliation: Worcester Polytechnic Institute, Worcester, Massachusetts 01609, USA.|Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
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authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
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authors.affiliation: Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
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authors.initials: AS
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authors.affiliation: Neuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.
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authors.initials: WS
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authors.affiliation: The Queen Elizabeth Hospital, Woodville South, South Australia 5011, Australia.
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authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia 30322, USA.
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authors.affiliation: Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Sermas 28041, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid 28029, Spain.
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authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
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authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.|Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK.|Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
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authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Nicola
authors.initials: N
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authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, 20122 Milan, Italy.
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authors.affiliation: Neuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.|School of Medical Sciences, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia.
authors.forename: John B J
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
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authors.affiliation: Medical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Robert H
authors.initials: RH
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authors.affiliation: Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Sermas 28041, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid 28029, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: García-Redondo
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
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authors.initials: R
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authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: John E
authors.initials: JE
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authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Aaron D
authors.identifier: http://orcid.org/0000-0001-8603-1526
authors.initials: AD
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authors.affiliation: Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.|Pathology and Cellular Biology Department, Montreal University, Montreal, QC H3T 1J4 Québec, Canada.
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cole
authors.affiliation: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.
authors.forename: Justin J
authors.identifier: http://orcid.org/0000-0003-2528-7039
authors.initials: JJ
authors.lastname: Yerbury
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Julie D
authors.initials: JD
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authors.affiliation: Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
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authors.initials: CE
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authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.|Molecular Medicine Laboratory, Concord Hospital, New South Wales 2139, Australia.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.|Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
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authors.initials: IP
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mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D016213:Cyclins / Q000235:genetics*; D005192:Family Health; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D017386:Sequence Homology, Amino Acid
chemical_list: C503669:CCNF protein, human; D016213:Cyclins