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

Gerald Pfeffer, Grace Lee, Carly S. Pontifex, Roberto D. Fanganiello, Allison Peck, Conrad C. Weihl, Virginia Kimonis

Research output: Contribution to journalReview articlepeer-review

31 Scopus citations

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.

Original languageEnglish
Article number963
JournalGenes
Volume13
Issue number6
DOIs
StatePublished - Jun 2022

Keywords

  • VCP
  • amyotrophic lateral sclerosis
  • dementia
  • genetics
  • genotype-phenotype correlation
  • multisystem proteinopathy
  • myopathy

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