Exome sequencing reveals VCP mutations as a cause of familial ALS

Jo Johnson, J Mandrioli, M Benatar, Y Abramzon, Vm Van Deerlin, Jq Trojanowski, Jr Gibbs, M Brunetti, S Gronka, J Wuu, J Ding, L Mccluskey, M Martinez Lage, D Falcone, Dg Hernandez, S Arepalli, S Chong, Jc Schymick, J Rothstein, Francesco Luigi LandiY Wang, A Calvo, G Mora, Mario Sabatelli, Monsurrò, S Battistini, F Salvi, R Spataro, P Sola, G Borghero, G Galassi, Sw Scholz, Jp Taylor, G Restagno, A Chiò, Bj Traynor

Risultato della ricerca: Contributo in rivistaArticolo in rivista

837 Citazioni (SciVal)


Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
Lingua originaleEnglish
pagine (da-a)857-864
Numero di pagine8
Stato di pubblicazionePubblicato - 2010


  • Adenosine Triphosphatases
  • Aged
  • Amino Acid Substitution
  • Amyotrophic Lateral Sclerosis
  • Case-Control Studies
  • Cell Cycle Proteins
  • Chromosomes, Human, Pair 9
  • Cohort Studies
  • Exons
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Reference Values


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