Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS


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.

DOI: 10.1016/j.neuron.2011.01.009

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@article{Johnson2010ExomeSR, title={Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS}, author={Janel O. Johnson and Jessica Mandrioli and Michael Benatar and Yevgeniya A Abramzon and Vivianna M. D. Van Deerlin and John Q. Trojanowski and Jesse Raphael Gibbs and Maura Brunetti and Susan Gronka and Joanne Wuu and Jinhui Ding and L. F. McCluskey and Maria Martinez-Lage and Dana Clay Falcone and Dena G. Hernandez and Sampath K Arepalli and Sean B Chong and Jennifer C. Schymick and Jeffrey D Rothstein and Francesco Landi and Yong-Dong Wang and Andrea Calvo and Gabriele Mora and Mario Sabatelli and Maria Rosaria Monsurr{\`o} and Stefania Battistini and Fabrizio Salvi and Rossella Spataro and Patrizia Sola and Giuseppe Borghero and Giuliana Galassi and Sonja W. Scholz and Joseph Taylor and Gabriella Restagno and Adriano Chi{\`o} and Bryan J. Traynor}, journal={Neuron}, year={2010}, volume={68}, pages={857-864} }