Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

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