Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis

Abstract

In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in VCP cause multisystem proteinopathy (VCP-MSP), an autosomal dominant, adult-onset disorder causing dysfunction in several tissue types. It can result in complex neurodegenerative conditions including inclusion body myopathy, frontotemporal dementia, amyotrophic lateral sclerosis, or combinations of these. There is also an association with other neurodegenerative phenotypes such as Alzheimer-type dementia and Parkinsonism. Non-neurological presentations include Paget disease of bone and may also include cardiac dysfunction. We provide a detailed discussion of genotype-phenotype correlations, recommendations for genetic diagnosis, and genetic counselling implications of VCP-MSP.

Keywords: VCP; amyotrophic lateral sclerosis; dementia; genetics; genotype-phenotype correlation; multisystem proteinopathy; myopathy.

Figure 1

Pathogenic mutations represented on the 3D model of VCP. (A) Three-dimensional representation of the VCP hexamer. We have color-coded individual domains from a single VCP monomer for ease of reference in subsequent images: Green for the N-terminal domain, blue for the N-D1 linker, yellow for the D1 domain, purple for the D1-D2 linker, light blue for the D2 domain, yellow for the C-terminal domain, with grey lines representing the other 5 structural oligomers. In red, we have represented the locations of pathogenic variants in VCP, showing the positions in the N-terminal domain (B), linker domain (C), D1 domain (D), and D2 domain (E). This figure was generated using open source material available from Swiss model [108] and PyMOL [109] based on the proposed structure of the VCP hexamer [110].