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CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Williams, KL, Topp, S, Yang, S, Smith, B, Fifita, JA, Warraich, ST, Zhang, KY, Farrawell, N, Vance, C, Hu, X, Chesi, A, Leblond, CS, Lee, A, Rayner, SL, Sundaramoorthy, V, Dobson-Stone, C, Molloy, MP, Van Blitterswijk, M, Dickson, DW, Petersen, RC, Graff-Radford, NR, Boeve, BF, Murray, ME, Pottier, C, Don, E, Winnick, C, McCann, EP, Hogan, A, Daoud, H, Levert, A, Dion, PA, Mitsui, J, Ishiura, H, Takahashi, Y, Goto, J, Kost, J, Gellera, C, Gkazi, AS, Miller, J, Stockton, J, Brooks, WS, Boundy, K, Polak, M, Muñoz-Blanco, JL, Esteban-Pérez, J, Rábano, A, Hardiman, O, Morrison, KE, Ticozzi, N, Silani, V, De Belleroche, J, Glass, JD, Kwok, JBJ, Guillemin, GJ, Chung, RS, Tsuji, S, Brown, RH, García-Redondo, A, Rademakers, R, Landers, JE, Gitler, AD, Rouleau, GA, Cole, NJ, Yerbury, JJ, Atkin, JD, Shaw, CE, Nicholson, GA and Blair, IP 2016, CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia, Nature Communications, vol. 7, pp. 1-8, doi: 10.1038/ncomms11253.

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Title CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
Author(s) Williams, KL
Topp, S
Yang, S
Smith, B
Fifita, JA
Warraich, ST
Zhang, KY
Farrawell, N
Vance, C
Hu, X
Chesi, A
Leblond, CS
Lee, A
Rayner, SL
Sundaramoorthy, VORCID iD for Sundaramoorthy, V orcid.org/0000-0001-6309-8031
Dobson-Stone, C
Molloy, MP
Van Blitterswijk, M
Dickson, DW
Petersen, RC
Graff-Radford, NR
Boeve, BF
Murray, ME
Pottier, C
Don, E
Winnick, C
McCann, EP
Hogan, A
Daoud, H
Levert, A
Dion, PA
Mitsui, J
Ishiura, H
Takahashi, Y
Goto, J
Kost, J
Gellera, C
Gkazi, AS
Miller, J
Stockton, J
Brooks, WS
Boundy, K
Polak, M
Muñoz-Blanco, JL
Esteban-Pérez, J
Rábano, A
Hardiman, O
Morrison, KE
Ticozzi, N
Silani, V
De Belleroche, J
Glass, JD
Kwok, JBJ
Guillemin, GJ
Chung, RS
Tsuji, S
Brown, RH
García-Redondo, A
Rademakers, R
Landers, JE
Gitler, AD
Rouleau, GA
Cole, NJ
Yerbury, JJ
Atkin, JD
Shaw, CE
Nicholson, GA
Blair, IP
Journal name Nature Communications
Volume number 7
Article ID 11253
Start page 1
End page 8
Total pages 8
Publisher Nature Research
Place of publication Berlin, Germany
Publication date 2016-04-15
ISSN 2041-1723
Keyword(s) Amyotrophic lateral sclerosis
Dementia
Disease genetics
Intracellular signalling peptides and proteins
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
UBIQUITIN-PROTEASOME SYSTEM
LOBAR DEGENERATION
PROTEIN
ALS
GENE
FRAMEWORK
STRESS
TDP-43
RNA
Summary 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.
Language eng
DOI 10.1038/ncomms11253
Indigenous content off
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2020, The Author(s)
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30136663

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.