CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Nat Commun. 2016 Apr 15;7:11253. doi: 10.1038/ncomms11253.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Cell Line, Tumor
  • Chromosome Mapping
  • Chromosomes, Human, Pair 16 / genetics
  • Cyclins / genetics*
  • Family Health
  • Female
  • Frontotemporal Dementia / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Sequence Analysis, DNA / methods
  • Sequence Homology, Amino Acid

Substances

  • CCNF protein, human
  • Cyclins