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 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 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 journalArticlepeer-review


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
Publication statusPublished - Apr 15 2016

ASJC Scopus subject areas

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


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