Valosin-containing protein disease: Inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia

Conrad C. Weihl, Alan Pestronk, Virginia E. Kimonis

Research output: Contribution to journalReview article

150 Scopus citations

Abstract

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD. Although IBMPFD is a multisystem disorder, muscle weakness is the presenting symptom in greater than half of patients and an isolated symptom in 30%. Patients with the full spectrum of the disease make up only 12% of those affected; therefore it is important to consider and recognize IBMPFD in a neuromuscular clinic. The current review describes the skeletal muscle phenotype and common muscle histochemical features in IBMPFD. In addition to myopathic features; vacuolar changes and tubulofilamentous inclusions are found in a subset of patients. The most consistent findings are VCP, ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions. VCP is a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to protein degradation. Although the role of VCP in skeletal muscle is currently unknown, it is clear that VCP mutations lead to the accumulation of ubiquitinated inclusions and protein aggregates in patient tissue, transgenic animals and in vitro systems. We suggest that IBMPFD is novel type of protein surplus myopathy. Instead of accumulating a poorly degraded and aggregated mutant protein as seen in some myofibrillar and nemaline myopathies, VCP mutations disrupt its normal role in protein homeostasis resulting in the accumulation of ubiquitinated and aggregated proteins that are deleterious to skeletal muscle.

Original languageEnglish
Pages (from-to)308-315
Number of pages8
JournalNeuromuscular Disorders
Volume19
Issue number5
DOIs
StatePublished - May 1 2009

Keywords

  • IBMPFD
  • Inclusion body
  • Inclusion body myopathy
  • Protein aggregates
  • Ubiquitin
  • VCP

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