VCP
Valosin-Containing Protein
Gene Summary
RefSeq / NCBIThis gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]
Clinical Phenotype
IBMPFD (Inclusion Body Myopathy with Paget disease of Bone and Frontotemporal Dementia): a multisystem proteinopathy. Not all three features are required. Mean age of onset is 45 years; most patients develop at least one component by age 60.
Molecular Mechanism
VCP/p97 is an AAA+ ATPase essential for ubiquitin-proteasome system and autophagy-mediated protein degradation. Mutations impair clearance of misfolded proteins, leading to accumulation of TDP-43 aggregates and rimmed vacuoles in muscle.
Clinical Hallmarks & Key Evidence
Rimmed vacuoles on muscle biopsy and TDP-43 positive inclusions are the histologic hallmarks — shared with sporadic inclusion body myositis (sIBM), but in a much younger patient with family history.
Watts GD et al. Nat Genet. 2004;36(4):377-81.
VCP disease belongs to the 'multisystem proteinopathy' spectrum that also includes Paget's disease of bone (elevated alkaline phosphatase, osteoclastic lesions on bone scan).
Kim HJ et al. Science. 2013;339(6115):1335. (TDP-43/FUS mutations cause similar spectrum)
Frontotemporal dementia in VCP disease often presents with behavioral variant FTD (disinhibition, apathy) rather than language-predominant variants — important for family counseling.
Johnson JO et al. Am J Hum Genet. 2010;87(5):711-17.
External Resources
Gene data compiled from the Washington University Neuromuscular Disease Center, NCBI Gene, and OMIM. For clinical use, always refer to primary sources.