title: Dominant-negative effects of a novel mutation in the filamin myopathy.
abstract: BACKGROUND
  Filamin myopathy is associated with mutations in the filamin C gene (FLNC) and is a myofibrillar myopathy characterized by focal myofibrillar destruction and cytoplasmic aggregates containing several Z-disk-related proteins.
  
  
  METHODS
  This study investigated 6 Japanese patients with dominantly inherited myofibrillar myopathy manifested by adult-onset, slow and progressive muscle weakness and atrophy in the distal extremities.
  
  
  RESULTS
  The abundantly expressed proteins in the affected muscles were identified as filamin C by nano liquid chromatography-tandem mass spectrometry. A genetic analysis of FLNC identified a heterozygous c.8107delG mutation that was localized to the dimerization domain of filamin C. A biochemical crosslinking analysis of bacterially expressed recombinant wild-type and mutant filamin C fragments demonstrated that the mutant monomer disturbed the proper dimerization of the wild-type filamin dimer, resulting in formation of a heterotrimer with the wild-type filamin dimer. The expression study in C2C12 myoblasts showed that the mutant filamin fragments formed cytoplasmic aggregates with endogenous wild-type filamin C.
  
  
  CONCLUSIONS
  This study provides evidence for the dominant-negative effects of the FLNC mutation. These effects may be mutation-specific and likely result in the variation in the clinical phenotypes seen in patients with filamin myopathy.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. satokono@hama-med.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Kono
authors.forename: T
authors.initials: T
authors.lastname: Nishio
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: N
authors.initials: N
authors.lastname: Goto-Inoue
authors.forename: M
authors.initials: M
authors.lastname: Kinoshita
authors.forename: N
authors.initials: N
authors.lastname: Zaima
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Fukutoku-Otsuji
authors.forename: M
authors.initials: M
authors.lastname: Setou
authors.forename: H
authors.initials: H
authors.lastname: Miyajima
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003285:Contractile Proteins / Q000235:genetics*; D005260:Female; D064448:Filamins; D017353:Gene Deletion; D005799:Genes, Dominant / Q000235:genetics*; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D032446:Myoblasts / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins