Exome sequencing reveals VCP mutations as a cause of familial ALS

By Janel O. Johnson, J. Mandrioli, M. Benatar, Yevgeniya A. Abramzon, V. Deerlin, John Q. Trojanowski, J. R. Gibbs, M. Brunetti, S. Gronka, J. Wuu and 26 more. Neuron, 2010

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Summary 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’s 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 represent the first evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.

Subfields: Neurology

View Paper: https://www.semanticscholar.org/paper/8c4e38afc3689ea91ce0fa0c90edf69110f38842

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Citations in the corpus

Mutations in the Profilin 1 Gene Cause Familial Amyotrophic Lateral Sclerosis (2012, positive): “To identify candidate causative mutations, variants were identified and filtered, as in previous exome sequencing reports 5 , using several criteria: the variant is observed in both family members, alters amino acid sequence, is not excluded by linkage analysis (Supplementary Fig.”
Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system (2012, background): “, but a subset of mutations are also associated with 1–2% of amyotrophic lateral sclerosis (ALS) case”
Amyotrophic lateral sclerosis: a clinical review (2020, background): “Several other mutations are found in genes involved in cargo recognition for the autophagy pathway, as they encode proteins that interact with the ubiquitinated cargo and the phagophore membrane: SQSTM1 (encoding the protein p62, which targets ubiquitinated proteins to the phagophore) [41], optineur”
Targeting RNA foci in iPSC-derived motor neurons from ALS patients with C9ORF72 repeat expansion (2013, background): “Mutations in several genes cause both disorders, including TARDBP (which encodes TDP-43) and VCP, although these are responsible for very few cases (6, 7).”
The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, positive): “…et al., 2010) TGM6 Spinocerebellar ataxia four family members (Wang et al., 2010) FADD Autoimmune lymphoproliferative syndrome one proband (Bolze et al., 2010) VCP Familial ALS two family members (Johnson et al., 2010) understanding of the molecular mechanisms by which mutations cause disease.”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “Furthermore, an association between the mutant forms of valosin-containing protein (VCP) with an autosomal dominant ALS has been observed (Johnson et al., 2010).”