title: Valosin-containing protein gene mutations: clinical and neuropathologic features.
abstract: BACKGROUND
  Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder with autosomal dominant inheritance. Recently, missense mutations in the gene encoding valosin-containing protein (VCP) have been found in individuals with IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retrotranslocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm.
  
  
  METHODS
  The authors describe the clinical features of two kindreds in which VCP R93C and R155C missense mutations segregate and perform a histopathologic examination of brain, muscle, bone, and liver of three subjects harboring the R155C mutation.
  
  
  RESULTS
  Frontotemporal dementia was present in 100% of affected subjects in Family F1 and 70% in Family F2, as compared with an average of 30% in previously described IBMPFD families. In contrast, PDB was a more inconstant clinical feature. Biochemical and histopathologic data are consistent with the hypothesis that VCP R155C mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells.
  
  
  CONCLUSIONS
  VCP mutations are present in two families in which FTD is the most prominent symptom. The histopathologic study performed in patients harboring the R155C mutation supports the hypothesis that this mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. IBMPFD belongs to a class of genetic diseases associated with an alteration of the ubiquitin-proteasome system.
authors.affiliation: Department of Neurology, Rouen University Hospital, France.
authors.forename: L
authors.initials: L
authors.lastname: Guyant-Maréchal
authors.forename: A
authors.initials: A
authors.lastname: Laquerrière
authors.forename: C
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: C
authors.initials: C
authors.lastname: Dumanchin
authors.forename: J
authors.initials: J
authors.lastname: Bou
authors.forename: F
authors.initials: F
authors.lastname: Dugny
authors.forename: I
authors.initials: I
authors.lastname: Le Ber
authors.forename: T
authors.initials: T
authors.lastname: Frébourg
authors.forename: D
authors.initials: D
authors.lastname: Hannequin
authors.forename: D
authors.initials: D
authors.lastname: Campion
mesh_terms: D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins / Q000235:genetics*; D025063:Chromosome Disorders / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D003704:Dementia / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000453:epidemiology / Q000235:genetics*; D010001:Osteitis Deformans / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D015995:Prevalence; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D013577:Syndrome; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein