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last update : 28-04-2014
Location 9p21.1-p12
Name inclusion body myopathy with early-onset Paget disease and frontotemporal dementia
Other name(s)
  • muscular dystrophy, limb-girdle, witih Paget disease of bone
  • Pagetoid amyotrophic lateral sclerosis
  • Pagetoid neuroskeletal syndrome
  • Corresponding gene VCP
    Main clinical features
  • muscle weakness and atrophy was progressive with mildly elevated to normal CPK levels and biopsy in the oldest male revealed vacuolated fibers or nonspecific aspect
  • neuropathological changes are ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites
  • Genetic determination autosomal dominant
    Related entries case associated to Frontotemporal lobar degeneration (Gitcho 2009)
    Function/system disorder osteo-articular
    Type disease
    Gene product
    Name valosin-containing protein
    Gene mutationChromosome rearrangementEffectComments
    missense     R155H, proeminent mutation, disrupting endoplasmic reticulum-associated degradation, and impairing cellular function
  • pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways
  • mutations in the VCP gene alter localization of TARDBP between the nucleus and cytosol, decrease proteasome activity, induce endoplasmic reticulum stress, increase markers of apoptosis, and impair cell viability (Gitcho 2009)
  • mutations identified thus far cluster within the NH2 domain or the D1 ring, which are both required for communicating conformational changes to adaptor protein complexes (Halawani 2009)
  • Genotype/Phenotype correlations
  • R155C had a reduced survival compared to the R155H (PMID: 22909335))