Title |
Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
|
---|---|
Published in |
Neuron, December 2010
|
DOI | 10.1016/j.neuron.2010.11.036 |
Pubmed ID | |
Authors |
Janel O. Johnson, Jessica Mandrioli, Michael Benatar, Yevgeniya Abramzon, Vivianna M. Van Deerlin, John Q. Trojanowski, J. Raphael Gibbs, Maura Brunetti, Susan Gronka, Joanne Wuu, Jinhui Ding, Leo McCluskey, Maria Martinez-Lage, Dana Falcone, Dena G. Hernandez, Sampath Arepalli, Sean Chong, Jennifer C. Schymick, Jeffrey Rothstein, Francesco Landi, Yong-Dong Wang, Andrea Calvo, Gabriele Mora, Mario Sabatelli, Maria Rosaria Monsurrò, Stefania Battistini, Fabrizio Salvi, Rossella Spataro, Patrizia Sola, Giuseppe Borghero, The ITALSGEN Consortium, Giuliana Galassi, Sonja W. Scholz, J. Paul Taylor, Gabriella Restagno, Adriano Chiò, Bryan J. Traynor |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 7 | <1% |
United Kingdom | 6 | <1% |
Germany | 2 | <1% |
Canada | 2 | <1% |
Norway | 1 | <1% |
Turkey | 1 | <1% |
India | 1 | <1% |
Finland | 1 | <1% |
Korea, Republic of | 1 | <1% |
Other | 4 | <1% |
Unknown | 890 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 213 | 23% |
Researcher | 146 | 16% |
Student > Bachelor | 110 | 12% |
Student > Master | 101 | 11% |
Student > Doctoral Student | 43 | 5% |
Other | 136 | 15% |
Unknown | 167 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 256 | 28% |
Biochemistry, Genetics and Molecular Biology | 167 | 18% |
Neuroscience | 136 | 15% |
Medicine and Dentistry | 110 | 12% |
Chemistry | 11 | 1% |
Other | 46 | 5% |
Unknown | 190 | 21% |