title: Exome sequencing reveals VCP mutations as a cause of familial ALS.
abstract: 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.
authors.affiliation: Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA.
authors.forename: Janel O
authors.initials: JO
authors.lastname: Johnson
authors.forename: Jessica
authors.initials: J
authors.lastname: Mandrioli
authors.forename: Michael
authors.initials: M
authors.lastname: Benatar
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Abramzon
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.forename: Susan
authors.initials: S
authors.lastname: Gronka
authors.forename: Joanne
authors.initials: J
authors.lastname: Wuu
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.forename: Dana
authors.initials: D
authors.lastname: Falcone
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.forename: Sampath
authors.initials: S
authors.lastname: Arepalli
authors.forename: Sean
authors.initials: S
authors.lastname: Chong
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Schymick
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rothstein
authors.forename: Francesco
authors.initials: F
authors.lastname: Landi
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.forename: Mario
authors.initials: M
authors.lastname: Sabatelli
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Monsurrò
authors.forename: Stefania
authors.initials: S
authors.lastname: Battistini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Salvi
authors.forename: Rossella
authors.initials: R
authors.lastname: Spataro
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sola
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
authors.forename: Giuliana
authors.initials: G
authors.lastname: Galassi
authors.forename: Sonja W
authors.initials: SW
authors.lastname: Scholz
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012016:Reference Values; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein