title: Characterization of the Asian myopathy patients with VCP mutations.
abstract: OBJECTIVE
  Mutations in the valosin-containing protein (VCP) gene are known to cause inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). Despite an increasing number of clinical reports, only one Asian family with IBMPFD has been described.
  
  
  METHODS
  To characterize patients with VCP mutations, we screened a total of 152 unrelated Asian families who were suspected to have rimmed vacuolar myopathy.
  
  
  RESULTS
  We identified VCP mutations in seven patients from six unrelated Asian families. Five different missense mutations were found, including a novel p.Ala439Pro substitution. All patients had adult-onset progressive muscle wasting with variable involvement of axial, proximal, and distal muscles. Two of seven patients were suggested to have mild brain involvement including cerebellar ataxia, and only one showed radiological findings indicating a change in bone. Findings from skeletal muscle indicated mixed neurogenic and myogenic changes, fibers with rimmed vacuoles, and the presence of cytoplasmic and nuclear inclusions. These inclusions were immunopositive for VCP, ubiquitin, transactivation response DNA-binding protein 43, and also histone deacetylase 6 (HDAC6), of which function is regulated by VCP. Evidence of early nuclear and mitochondrial damage was also characteristic.
  
  
  CONCLUSIONS
  Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.
authors: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.
authors: Z
authors: Z
authors: Shi
authors: Y K
authors: YK
authors: Hayashi
authors: S
authors: S
authors: Mitsuhashi
authors: K
authors: K
authors: Goto
authors: D
authors: D
authors: Kaneda
authors: Y-C
authors: YC
authors: Choi
authors: C
authors: C
authors: Toyoda
authors: S
authors: S
authors: Hieda
authors: T
authors: T
authors: Kamiyama
authors: H
authors: H
authors: Sato
authors: M
authors: M
authors: Wada
authors: S
authors: S
authors: Noguchi
authors: I
authors: I
authors: Nonaka
authors: I
authors: I
authors: Nishino
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein