Evidence map›Paper›PMID 27080313›Full record

ArticleNature communications2016

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 and 58 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
117citing papers in PubMed, 5 pooled it
18.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

117 citing papers in PubMed, 5 syntheses or guidelines pooled it, 207 citations in OpenAlex.

  1. Pooled it
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  8. ALS-FTD-linked CCNFJournal of neuroinflammation · 2026
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57 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

68 authors at 20 institutions in 8 countries.

Kelly L WilliamsDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.ORCID http://orcid.org/0000-0001-6319-9473
Simon ToppMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.ORCID http://orcid.org/0000-0002-5200-3284
Shu YangDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Bradley SmithMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Jennifer A FifitaDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Sadaf T WarraichDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Katharine Y ZhangDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Natalie FarrawellIllawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.
Caroline VanceMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Xun HuMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Alessandra ChesiDepartment of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Claire S LeblondMontreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.
Albert LeeDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.ORCID http://orcid.org/0000-0001-5156-0567
Stephanie L RaynerDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Vinod SundaramoorthyDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Carol Dobson-StoneNeuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.
Mark P MolloyDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Marka van BlitterswijkDepartment of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.ORCID http://orcid.org/0000-0001-7189-7917
Ronald C PetersenDepartment of Neurology, Mayo Clinic Rochester, Rochester, Minneapolis 55905, USA.
Neill R Graff-RadfordDepartment of Neurology, Mayo Clinic Florida, Jacksonville, Florida, 32224, USA.
Bradley F BoeveDepartment of Neurology, Mayo Clinic Rochester, Rochester, Minneapolis 55905, USA.
Melissa E MurrayDepartment of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.ORCID http://orcid.org/0000-0001-7379-2545
Cyril PottierDepartment of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
Emily DonDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Claire WinnickDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Emily P McCannDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Alison HoganDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Hussein DaoudMontreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.
Annie LevertMontreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.
Patrick A DionMontreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.
Jun MitsuiMedical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
Hiroyuki IshiuraMedical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
Yuji TakahashiMedical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
Jun GotoMedical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
Jason KostWorcester Polytechnic Institute, Worcester, Massachusetts 01609, USA.
Cinzia GelleraUnit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
Athina Soragia GkaziMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Jack MillerMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Joanne StocktonSchool of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
William S BrooksNeuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.
Karyn BoundyThe Queen Elizabeth Hospital, Woodville South, South Australia 5011, Australia.
Meraida PolakDepartment of Neurology, Emory University, Atlanta, Georgia 30322, USA.
José Luis Muñoz-BlancoUnidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, Sermas 28007, Spain.
Jesús Esteban-PérezUnidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Sermas 28041, Spain.
Alberto RábanoBanco de Tejidos, Centro Alzheimer-Fundación Reina Sofia, Fundación CIEN, Madrid 28071, Spain.
Orla HardimanAcademic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
Karen E MorrisonSchool of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Nicola TicozziDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
Vincenzo SilaniDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
Jacqueline de BellerocheNeurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
Jonathan D GlassDepartment of Neurology, Emory University, Atlanta, Georgia 30322, USA.
John B J KwokNeuroscience Research Australia, Randwick, Sydney, New South Wales 2031, Australia.
Gilles J GuilleminDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.ORCID http://orcid.org/0000-0001-8105-4470
Roger S ChungDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Shoji TsujiMedical Genome Center, The University of Tokyo Hospital, The University of Tokyo, Tokyo 113-8655, Japan.
Robert H BrownDepartment of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Alberto García-RedondoUnidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, Sermas 28041, Spain.
Rosa RademakersDepartment of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.
John E LandersDepartment of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Aaron D GitlerDepartment of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.ORCID http://orcid.org/0000-0001-8603-1526
Guy A RouleauMontreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.
Nicholas J ColeDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Justin J YerburyIllawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.ORCID http://orcid.org/0000-0003-2528-7039
Julie D AtkinDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Christopher E ShawMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Garth A NicholsonDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Ian P BlairDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Macquarie University · AUKing's College London · GBJacksonville College · USMontreal Neurological Institute and Hospital · CAUniversity of Tokyo Hospital · JPAnzac Research Institute · AUThe University of Sydney · AUAGRF Ltd · AUEmory University · USLa Trobe University · AUMayo Clinic · USResearch Institute Hospital 12 de Octubre · ESStanford University · USUniversity of Massachusetts Chan Medical School · USUniversity of Milan · ITUniversity of Wollongong · AUUNSW Sydney · AUFondazione IRCCS Istituto Neurologico Carlo Besta · ITFundacion Centro De Investigacion De Enfermedades Neurologicas · ESHammersmith Hospital · GB

Funding

Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Richard B. LIPTON · 1985 to 2026
$73.9M
THE PGRN/TDP-43 AXIS IN ALZHEIMER?S DISEASE AND NEURODEGENERATIONP50AG016574 · NIA · MAYO CLINIC ROCHESTER · PI BU, GUOJUN · 1999 to 2018
$36.9M
Neuropathology CoreP50NS072187 · NINDS · MAYO CLINIC JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 2010 to 2017
$8.7M
Identification of genes causative for familial ALS gene using exome sequencingR01NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2011 to 2019
$4.6M
Full Human Genome Sequencing in ALSRC2NS070342 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI BROWN, ROBERT H. · 2009 to 2010
$3.6M
Molecular Basis of TDP-43 Proteinopathies: Disease Models and MechanismsR01NS065317 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI GITLER, AARON D. · 2009 to 2016
$2.7M
High-Throughput Genomic Approaches to Identify ALS GenesR01NS050557 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI BROWN, ROBERT H. · 2005 to 2009
$2.5M
The genetics of chromosome 17q21-linked tau-negative FTDR01AG026251 · NIA · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2006 to 2014
$1.9M
Molecular genetic studies of progranulin regulators in FTLD and ALSR01NS076471 · NINDS · MAYO CLINIC JACKSONVILLE · PI RADEMAKERS, ROSA · 2013 to 2016
$1.4M
CIHR 208973Medical Research CouncilMotor Neurone Disease Association SMITH/APR16/847-791MRF_ MRF-060-0003-RG-SMITHNIA NIH HHS P01 AG003949NIA NIH HHS P01 AG03949NIA NIH HHS P50 AG016574NIA NIH HHS R01 AG026251NIH HHS 1DP2OD0044171NINDS NIH HHS 1R01NS050557NINDS NIH HHS P50 NS072187NINDS NIH HHS P50 NS72187NINDS NIH HHS R01 NS050557NINDS NIH HHS R01 NS065317NINDS NIH HHS R01 NS073873NINDS NIH HHS R01NS073873NINDS NIH HHS R01 NS076471NINDS NIH HHS RC2 NS070342NINDS NIH HHS RC2-NS070-342
6 · The paper itself

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.

Indexed as

Mutation, MissenseAdultAgedAmino Acid SequenceAmyotrophic Lateral SclerosisAnimalsCell Line, TumorChromosome MappingChromosomes, Human, Pair 16CyclinsFamily HealthFemaleFrontotemporal DementiaGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansCCNF protein, humanCyclins

Identifiers

PMID27080313
PMCPMC4835537
OpenAlexW2340895726

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.