Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Open accessAbstract
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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p97/VCP mutation is directly linked to human neuromuscular diseases like Inclusion Body Myopathy, Frontotemporal dementia, and Amyotrophic Lateral Sclerosis.
“The relevance of mitochondrial retrotranslocation mechanism in quality control has been demonstrated by the direct link between p97/VCP mutation and human neuromuscular diseases, like Inclusion Body Myopathy, Frontotemporal dementia and Amyotrophic Lateral Sclerosis [171, 172].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [172]
VCP mutations are responsible for approximately 1-2% of familial ALS cases.
“but are also responsible for ~1-2% of familial ALS cases [241–243].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [243]
Genetic deletion of central (e.g., VCP) or ancillary regulators of the autophagic cascade (e.g., GRN/progranulin, ALS2/alsin-2) precipitate ALS symptomatology in mice and human patients.
“The strict nexus between ALS and autophagy is further strengthened by experimental evidence indicating that genetic deletion of central (e.g., VCP) (Johnson et al, 2010) or ancillary regulators of the autophagic cascade (e.g., GRN/progranulin, ALS2/alsin‐2) precipitate ALS symptomatology in mice and human patients (Yang et al, 2001; Chang et al, 2017).”
From Autophagy in major human diseases (2021) · cites this paper as Johnson et al, 2010
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References 43 · Cited by 1,235
- Authors
- Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., Martinez-Lage, M., Falcone, D., Hernandez, D. G., Arepalli, S., Chong, S., Schymick, J. C., Rothstein, J., Landi, F., Wang, Y.-D., Calvo, A., Mora, G., Sabatelli, M., Monsurrò, M. R., Battistini, S., Salvi, F., Spataro, R., Sola, P., Borghero, G., Galassi, G., Scholz, S. W., Taylor, J. P., Restagno, G., Chiò, A., & Traynor, B. J.
- Affiliations
- National Institutes of Health (US)
- University of Modena and Reggio Emilia (IT)
- Emory University (US)
- University of Pennsylvania (US)
- Ospedale Sant'Anna (IT)
- Johns Hopkins University (US)
- Università Cattolica del Sacro Cuore (IT)
- St. Jude Children's Research Hospital (US)
- University of Turin (IT)
- Fondazione Salvatore Maugeri (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- University of Siena (IT)
- Ospedale Bellaria (IT)
- University of Palermo (IT)
- University of Cagliari (IT)
- Corresponding author
- Traynor, Bryan J.
- ORCID
- Mandrioli, Jessica
- Benatar, Michael
- Trojanowski, John Q.
- Gibbs, J. Raphael
- Brunetti, Maura
- Wuu, Joanne
- Ding, Jinhui
- Falcone, Dana
- Hernandez, Dena G.
- Schymick, Jennifer C.
- Rothstein, Jeffrey
- Landi, Francesco
- Wang, Yong-Dong
- Calvo, Andrea
- Mora, Gabriele
- Sabatelli, Mario
- Monsurrò, Maria Rosaria
- Battistini, Stefania
- Spataro, Rossella
- Sola, Patrizia
- Borghero, Giuseppe
- Galassi, Giuliana
- Scholz, Sonja W.
- Taylor, J. Paul
- Chiò, Adriano
- Traynor, Bryan J.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 68
- Issue
- 5
- Pages
- 857-864
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3032425
- OpenAlex
- W1983633543
- Cited by
- 1,235
- References
- 43
- Citations by year
- 2026: 27 · 2025: 36 · 2024: 47 · 2023: 56 · 2022: 49 · 2021: 77 · 2020: 84 · 2019: 63 · 2018: 77 · 2017: 96 · 2016: 99 · 2015: 94 · 2014: 102 · 2013: 111 · 2012: 120
- FWCI
- 61.84
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-01-27)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- National Parkinson Foundation
- National Institutes of Health (Z01-AG000949)
- National Institute on Aging (P01AG017586, AG17586, P50AG008702, Z01AG000949, ZIAAG000933, P50AG08702)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- VCP, VCP mutations, familial ALS, autosomal dominant inheritance, TDP-43, ubiquitination, autophagy, protein degradation, motor neuron degeneration, genetic screening
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Aged, Amyotrophic Lateral Sclerosis, Chromosomes, Human, Pair 9, Exons, Female, Humans, Male, Middle Aged, Mutation, Pedigree, Reference Values, Cohort Studies, Case-Control Studies, Cell Cycle Proteins, Amino Acid Substitution
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