6533b86dfe1ef96bd12c9672
RESEARCH PRODUCT
Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Janel O. JohnsonJessica MandrioliMichael BenatarYevgeniya AbramzonVivianna M. Van DeerlinJohn Q. TrojanowskiJ. Raphael GibbsMaura BrunettiSusan GronkaJoanne WuuJinhui DingLeo MccluskeyMaria Martinez LageDana FalconeDena G. HernandezSampath ArepalliSean ChongJennifer C. SchymickJeffrey RothsteinFrancesco LandiYong Dong WangAndrea CalvoGabriele MoraMario SabatelliStefania BattistiniFabrizio SalviRossella SpataroPatrizia SolaGiuseppe BorgheroFabio GianniniClaudia RicciCristina MogliaIrene OssolaAntonio CanosaSara GalloPatrizia SolaIlaria BartolomeiKalliopi MarinouLaura PapettiAmelia ConteMarco LuigettiVincenzo La BellaPiera PaladinoClaudia CaponnettoPaolo VolantiMaria Teresa MarrosuMaria Rita MurruGiuliana GalassiSonja W. ScholzJ. Paul TaylorGabriella RestagnoAdriano ChiòBryan J. TraynorMaria Rosaria Monsurro'Gioacchino Tedeschisubject
Adenosine TriphosphataseMaleCell Cycle ProteinsUBQLN2Cohort Studies0302 clinical medicineReference ValuesValosin Containing ProteinCell Cycle ProteinReference ValueAmyotrophic lateral sclerosisExome sequencingAdenosine TriphosphatasesGenetics0303 health sciencesGeneral NeuroscienceExonsMiddle AgedPedigree3. Good healthMultisystem proteinopathyFemaleSettore MED/26 - NeurologiaCase-Control StudieChromosomes Human Pair 9HumanFrontotemporal dementiaNeuroscience(all)Valosin-containing proteinExonBiologyProtein degradationTARDBPArticle03 medical and health sciencesmedicineHumansAged030304 developmental biologyAmyotrophic lateral sclerosis familial ALS exome sequencingNeuroscience (all)business.industryAmyotrophic Lateral Sclerosismedicine.diseaseAmino Acid SubstitutionCase-Control StudiesMutationbiology.proteinCohort Studiebusiness030217 neurology & neurosurgeryAmyotrophic Lateral Sclerosidescription
Summary 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2010-12-01 | Neuron |