CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Kelly L. Williams, Simon Topp, Shu Yang, Bradley N. 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 Petersen & 48 others 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 E. Kost, Cinzia Gellera, Athina Gkazi, Jack Miller, Joanne D. Stockton, William S. Brooks, Karyn Boundy, Meraida Polak, José Luis Muñoz-Blanco, Jesús Esteban-Pérez, Alberto Rabano, 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 Garcia Redondo, Rosa Rademakers, John Landers, Aaron D. Gitler, Guy A. Rouleau, Nicholas J. Cole, Justin J. Yerbury, Julie D. Atkin, Christopher E. Shaw, Garth Nicholson, Ian P. Blair

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number11253
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Apr 15 2016

Fingerprint

Ubiquitinated Proteins
mutations
Ubiquitin-Protein Ligase Complexes
proteins
Mutation
Cyclins
Chromosomes
Exome
Frontotemporal Dementia
loci
Proteins
Genes
Ubiquitination
Missense Mutation
Neurodegenerative Diseases
Homeostasis
Substrates
homeostasis
sequencing
Genome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Williams, K. L., Topp, S., Yang, S., Smith, B. N., Fifita, J. A., Warraich, S. T., ... Blair, I. P. (2016). CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nature Communications, 7, [11253]. https://doi.org/10.1038/ncomms11253

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. / Williams, Kelly L.; Topp, Simon; Yang, Shu; Smith, Bradley N.; Fifita, Jennifer A.; Warraich, Sadaf T.; Zhang, Katharine Y.; Farrawell, Natalie; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S.; Lee, Albert; Rayner, Stephanie L.; Sundaramoorthy, Vinod; Dobson-Stone, Carol; Molloy, Mark P.; Van Blitterswijk, Marka; Dickson, Dennis W.; Petersen, Ronald; Graff-Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Pottier, Cyril; Don, Emily; Winnick, Claire; McCann, Emily P.; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A.; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Kost, Jason E.; Gellera, Cinzia; Gkazi, Athina; Miller, Jack; Stockton, Joanne D.; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rabano, Alberto; Hardiman, Orla; Morrison, Karen E.; Ticozzi, Nicola; Silani, Vincenzo; De Belleroche, Jacqueline; Glass, Jonathan D.; Kwok, John B J; Guillemin, Gilles J.; Chung, Roger S.; Tsuji, Shoji; Brown, Robert H.; Garcia Redondo, Alberto; Rademakers, Rosa; Landers, John; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth; Blair, Ian P.

In: Nature Communications, Vol. 7, 11253, 15.04.2016.

Research output: Contribution to journalArticle

Williams, KL, Topp, S, Yang, S, Smith, BN, 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, R, 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, JE, Gellera, C, Gkazi, A, Miller, J, Stockton, JD, Brooks, WS, Boundy, K, Polak, M, Muñoz-Blanco, JL, Esteban-Pérez, J, Rabano, A, Hardiman, O, Morrison, KE, Ticozzi, N, Silani, V, De Belleroche, J, Glass, JD, Kwok, JBJ, Guillemin, GJ, Chung, RS, Tsuji, S, Brown, RH, Garcia Redondo, A, Rademakers, R, Landers, J, Gitler, AD, Rouleau, GA, Cole, NJ, Yerbury, JJ, Atkin, JD, Shaw, CE, Nicholson, G & Blair, IP 2016, 'CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia', Nature Communications, vol. 7, 11253. https://doi.org/10.1038/ncomms11253
Williams KL, Topp S, Yang S, Smith BN, Fifita JA, Warraich ST et al. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nature Communications. 2016 Apr 15;7. 11253. https://doi.org/10.1038/ncomms11253
Williams, Kelly L. ; Topp, Simon ; Yang, Shu ; Smith, Bradley N. ; Fifita, Jennifer A. ; Warraich, Sadaf T. ; Zhang, Katharine Y. ; Farrawell, Natalie ; Vance, Caroline ; Hu, Xun ; Chesi, Alessandra ; Leblond, Claire S. ; Lee, Albert ; Rayner, Stephanie L. ; Sundaramoorthy, Vinod ; Dobson-Stone, Carol ; Molloy, Mark P. ; Van Blitterswijk, Marka ; Dickson, Dennis W. ; Petersen, Ronald ; Graff-Radford, Neill R. ; Boeve, Bradley F. ; Murray, Melissa E. ; Pottier, Cyril ; Don, Emily ; Winnick, Claire ; McCann, Emily P. ; Hogan, Alison ; Daoud, Hussein ; Levert, Annie ; Dion, Patrick A. ; Mitsui, Jun ; Ishiura, Hiroyuki ; Takahashi, Yuji ; Goto, Jun ; Kost, Jason E. ; Gellera, Cinzia ; Gkazi, Athina ; Miller, Jack ; Stockton, Joanne D. ; Brooks, William S. ; Boundy, Karyn ; Polak, Meraida ; Muñoz-Blanco, José Luis ; Esteban-Pérez, Jesús ; Rabano, Alberto ; Hardiman, Orla ; Morrison, Karen E. ; Ticozzi, Nicola ; Silani, Vincenzo ; De Belleroche, Jacqueline ; Glass, Jonathan D. ; Kwok, John B J ; Guillemin, Gilles J. ; Chung, Roger S. ; Tsuji, Shoji ; Brown, Robert H. ; Garcia Redondo, Alberto ; Rademakers, Rosa ; Landers, John ; Gitler, Aaron D. ; Rouleau, Guy A. ; Cole, Nicholas J. ; Yerbury, Justin J. ; Atkin, Julie D. ; Shaw, Christopher E. ; Nicholson, Garth ; Blair, Ian P. / CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. In: Nature Communications. 2016 ; Vol. 7.
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