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 Carl PetersenNeill 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 V 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, Ian P. Blair

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 (US)
Article number11253
JournalNature Communications
Volume7
DOIs
StatePublished - 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., 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; 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 Carl; 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; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack; Stockton, Joanne; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rábano, 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.; García-Redondo, Alberto; Rademakers, Rosa V; Landers, John E.; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth A.; Blair, Ian P.

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

Research output: Contribution to journalArticle

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, RV, Landers, JE, Gitler, AD, Rouleau, GA, Cole, NJ, Yerbury, JJ, Atkin, JD, Shaw, CE, Nicholson, GA & 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 B, 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 ; 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 Carl ; 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 ; Gellera, Cinzia ; Gkazi, Athina Soragia ; Miller, Jack ; Stockton, Joanne ; Brooks, William S. ; Boundy, Karyn ; Polak, Meraida ; Muñoz-Blanco, José Luis ; Esteban-Pérez, Jesús ; Rábano, 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. ; García-Redondo, Alberto ; Rademakers, Rosa V ; Landers, John E. ; Gitler, Aaron D. ; Rouleau, Guy A. ; Cole, Nicholas J. ; Yerbury, Justin J. ; Atkin, Julie D. ; Shaw, Christopher E. ; Nicholson, Garth A. ; Blair, Ian P. / CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. In: Nature Communications. 2016 ; Vol. 7.
@article{c544ae844d6243479e2c8bedbf602965,
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 (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.",
author = "Williams, {Kelly L.} and Simon Topp and Shu Yang and Bradley Smith and Fifita, {Jennifer A.} and Warraich, {Sadaf T.} and Zhang, {Katharine Y.} and Natalie Farrawell and Caroline Vance and Xun Hu and Alessandra Chesi and Leblond, {Claire S.} and Albert Lee and Rayner, {Stephanie L.} and Vinod Sundaramoorthy and Carol Dobson-Stone and Molloy, {Mark P.} and {Van Blitterswijk}, Marka and Dickson, {Dennis W} and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Boeve, {Bradley F} and Murray, {Melissa E} and Cyril Pottier and Emily Don and Claire Winnick and McCann, {Emily P.} and Alison Hogan and Hussein Daoud and Annie Levert and Dion, {Patrick A.} and Jun Mitsui and Hiroyuki Ishiura and Yuji Takahashi and Jun Goto and Jason Kost and Cinzia Gellera and Gkazi, {Athina Soragia} and Jack Miller and Joanne Stockton and Brooks, {William S.} and Karyn Boundy and Meraida Polak and Mu{\~n}oz-Blanco, {Jos{\'e} Luis} and Jes{\'u}s Esteban-P{\'e}rez and Alberto R{\'a}bano and Orla Hardiman and Morrison, {Karen E.} and Nicola Ticozzi and Vincenzo Silani and {De Belleroche}, Jacqueline and Glass, {Jonathan D.} and Kwok, {John B J} and Guillemin, {Gilles J.} and Chung, {Roger S.} and Shoji Tsuji and Brown, {Robert H.} and Alberto Garc{\'i}a-Redondo and Rademakers, {Rosa V} and Landers, {John E.} and Gitler, {Aaron D.} and Rouleau, {Guy A.} and Cole, {Nicholas J.} and Yerbury, {Justin J.} and Atkin, {Julie D.} and Shaw, {Christopher E.} and Nicholson, {Garth A.} and Blair, {Ian P.}",
year = "2016",
month = "4",
day = "15",
doi = "10.1038/ncomms11253",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

AU - Williams, Kelly L.

AU - Topp, Simon

AU - Yang, Shu

AU - Smith, Bradley

AU - Fifita, Jennifer A.

AU - Warraich, Sadaf T.

AU - Zhang, Katharine Y.

AU - Farrawell, Natalie

AU - Vance, Caroline

AU - Hu, Xun

AU - Chesi, Alessandra

AU - Leblond, Claire S.

AU - Lee, Albert

AU - Rayner, Stephanie L.

AU - Sundaramoorthy, Vinod

AU - Dobson-Stone, Carol

AU - Molloy, Mark P.

AU - Van Blitterswijk, Marka

AU - Dickson, Dennis W

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Boeve, Bradley F

AU - Murray, Melissa E

AU - Pottier, Cyril

AU - Don, Emily

AU - Winnick, Claire

AU - McCann, Emily P.

AU - Hogan, Alison

AU - Daoud, Hussein

AU - Levert, Annie

AU - Dion, Patrick A.

AU - Mitsui, Jun

AU - Ishiura, Hiroyuki

AU - Takahashi, Yuji

AU - Goto, Jun

AU - Kost, Jason

AU - Gellera, Cinzia

AU - Gkazi, Athina Soragia

AU - Miller, Jack

AU - Stockton, Joanne

AU - Brooks, William S.

AU - Boundy, Karyn

AU - Polak, Meraida

AU - Muñoz-Blanco, José Luis

AU - Esteban-Pérez, Jesús

AU - Rábano, Alberto

AU - Hardiman, Orla

AU - Morrison, Karen E.

AU - Ticozzi, Nicola

AU - Silani, Vincenzo

AU - De Belleroche, Jacqueline

AU - Glass, Jonathan D.

AU - Kwok, John B J

AU - Guillemin, Gilles J.

AU - Chung, Roger S.

AU - Tsuji, Shoji

AU - Brown, Robert H.

AU - García-Redondo, Alberto

AU - Rademakers, Rosa V

AU - Landers, John E.

AU - Gitler, Aaron D.

AU - Rouleau, Guy A.

AU - Cole, Nicholas J.

AU - Yerbury, Justin J.

AU - Atkin, Julie D.

AU - Shaw, Christopher E.

AU - Nicholson, Garth A.

AU - Blair, Ian P.

PY - 2016/4/15

Y1 - 2016/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84964430150&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964430150&partnerID=8YFLogxK

U2 - 10.1038/ncomms11253

DO - 10.1038/ncomms11253

M3 - Article

C2 - 27080313

AN - SCOPUS:84964430150

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11253

ER -