CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

• Published in: Nature communications Vol. 7; no. 1; pp. 11253 - 8
• Main Authors: 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 C., 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, 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/2489/144; 631/45/612/1234; 692/699/375/132; 692/699/375/365/1917/1285; 82/80; Adult; Aged; Amino Acid Sequence; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Cell Line, Tumor; Chromosome Mapping; Chromosomes, Human, Pair 16 - genetics; Cyclins - genetics; Dementia; Dementia disorders; Family Health; Female; Frontotemporal Dementia - genetics; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Hospitals; Humanities and Social Sciences; Humans; Male; Medical research; Medicine; Middle Aged; multidisciplinary; Mutation; Mutation, Missense; Neurology; Neurosciences; Pedigree; Proteins; Science; Science (multidisciplinary); Sequence Analysis, DNA - methods; Sequence Homology, Amino Acid; Canada; United Kingdom > UK; United States > US; Massachusetts; Japan; Italy; Montreal Quebec Canada; Australia; Florida; New South Wales Australia; Spain
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11253

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. Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNF gene product affects ubiquitination and protein degradation in cultured cells.