CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
Citation:
Williams K.L., Topp, S., Yang, S., Smith, B., Fifita, J.A., Warraich, S.T., Zhang, K.Y., Farrawell, N., Vance, C., Hu, X., Chesi, A., Leblond, C.S., Lee, A., Rayner, S.L., Sundaramoorthy, V., Dobson-Stone, C., Molloy, M.P., Van Blitterswijk, M., Dickson, D.W., Petersen, R.C., Graff-Radford, N.R., Boeve, B.F., Murray, M.E., Pottier, C., Don, E., Winnick, C., McCann, E.P., Hogan, A., Daoud, H., Levert, A., Dion, P.A., Mitsui, J., Ishiura, H., Takahashi, Y., Goto, J., Kost, J., Gellera, C., Gkazi, A.S., Miller, J., Stockton, J., Brooks, W.S., Boundy, K., Polak, M., Muñoz-Blanco, J.L., Esteban-Perez, J., Rabano, A., Hardiman, O., Morrison, K.E., Ticozzi, N., Silani, V., De Belleroche, J., Glass, J.D., Kwok, J.B.J., Guillemin, G.J., Chung, R.S., Tsuji, S., Brown, R.H., Garcia-Redondo, A., Rademakers, R., Landers, J.E., Gitler, A.D., Rouleau, G.A., Cole, N.J., Yerbury, J.J., Atkin, J.D., Shaw, C.E., Nicholson, G.A., Blair, I.P. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia, Nature Communications, 2016, 7, 11253Download Item:
Abstract:
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neuro-degenerative 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 aSCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
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http://people.tcd.ie/hardimao
Author: Hardiman, Orla
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Journal ArticleCollections
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Nature Communications;7;
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Full text availableKeywords:
Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), Neuro-degenerative disorders, Ubiquitinated proteins, Protein homeostasis, Neuronal degenerationDOI:
http://dx.doi.org/10.1038/ncomms11253Metadata
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