TY - JOUR
T1 - Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
AU - Johnson, Janel O.
AU - Mandrioli, Jessica
AU - Benatar, Michael
AU - Abramzon, Yevgeniya
AU - Van Deerlin, Vivianna M.
AU - Trojanowski, John Q.
AU - Gibbs, J. Raphael
AU - Brunetti, Maura
AU - Gronka, Susan
AU - Wuu, Joanne
AU - Ding, Jinhui
AU - McCluskey, Leo
AU - Martinez-Lage, Maria
AU - Falcone, Dana
AU - Hernandez, Dena G.
AU - Arepalli, Sampath
AU - Chong, Sean
AU - Schymick, Jennifer C.
AU - Rothstein, Jeffrey
AU - Landi, Francesco
AU - Wang, Yong Dong
AU - Calvo, Andrea
AU - Mora, Gabriele
AU - Sabatelli, Mario
AU - Monsurrò, Maria Rosaria
AU - Battistini, Stefania
AU - Salvi, Fabrizio
AU - Spataro, Rossella
AU - Sola, Patrizia
AU - Borghero, Giuseppe
AU - Galassi, Giuliana
AU - Scholz, Sonja W.
AU - Taylor, J. Paul
AU - Restagno, Gabriella
AU - Chiò, Adriano
AU - Traynor, Bryan J.
N1 - Funding Information:
This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02), and NINDS. The work was also funded by the Packard Center for ALS Research at Hopkins, the Fondazione Vialli e Mauro for ALS Research Onlus, Federazione Italiana Giuoco Calcio (FIGC), the Ministero della Salute (Ricerca Sanitaria Finalizzata 2007), the Muscular Dystrophy Association (Grant 4365), and the Woodruff Health Sciences Center at Emory University. DNA samples for this study were obtained in part from the NINDS repository at the Coriell Cell Repositories ( http://www.coriell.org/ ). We gratefully acknowledge the assistance of the New York Brain Bank: The Taub Institute, Columbia University (Federal grant No. P50 AG08702) and the University of Miami/National Parkinson Foundation Brain Endowment Bank. This work was supported by funding from the NIH (AG17586). J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr. Professor of Geriatric Medicine and Gerontology. J.R. is Director of the Packard Center for ALS Research at Hopkins. None of the other authors have any conflicts of interest. We thank the patients and research subjects who contributed samples for this study.
PY - 2010/12/9
Y1 - 2010/12/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2010.11.036
DO - 10.1016/j.neuron.2010.11.036
M3 - Article
C2 - 21145000
AN - SCOPUS:78649941297
VL - 68
SP - 857
EP - 864
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 5
ER -