CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Hardiman, Orla

doi:http://dx.doi.org/10.1038/ncomms11253

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

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Date

2016

Authors

Hardiman, Orla

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openAccess

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, 11253

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.