CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.
Kelly Louise WilliamsSimon D ToppShu YangBradley SmithJennifer A FifitaSadaf T WarraichKatharine Y ZhangNatalie FarrawellCaroline VanceXun HuAlessandra ChesiClaire S LeblondAlbert LeeStephanie L RaynerVinod SundaramoorthyCarol Dobson-StoneMark P MolloyMarka van BlitterswijkGourisankar GhoshRonald C PetersenNeill R Graff-RadfordBradley F BoeveMelissa E MurrayCyril PottierEmily DonClaire WinnickEmily P McCannAlison HoganHussein DaoudAnnie LevertPatrick A DionJun MitsuiHiroyuki IshiuraYuji TakahashiJun GotoJason KostCinzia GelleraAthina Soragia GkaziJack MillerJoanne StocktonWilliam S BrooksKaryn BoundyMeraida PolakJosé Luis Muñoz-BlancoJesús Esteban-PérezAlberto RábanoOrla HardimanKaren E MorrisonNicola TicozziVincenzo SilaniJacqueline de BellerocheJonathan D GlassJohn B J KwokGilles J GuilleminRoger S ChungShoji TsujiRobert H BrownAlberto García-RedondoRosa RademakersJohn E LandersAaron D GitlerGuy A RouleauNicholas J ColeJustin J YerburyJulie D AtkinChristopher E ShawGarth A NicholsonIan P BlairPublished in: Nature communications (2016)
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.
Keyphrases
- amyotrophic lateral sclerosis
- genome wide
- copy number
- cell cycle arrest
- protein protein
- binding protein
- amino acid
- poor prognosis
- end stage renal disease
- dna methylation
- newly diagnosed
- chronic kidney disease
- ejection fraction
- induced apoptosis
- gene expression
- signaling pathway
- cell proliferation
- intellectual disability
- single molecule
- genome wide association study
- long non coding rna
- pi k akt
- high density