title: Metavinculin mutations alter actin interaction in dilated cardiomyopathy.
abstract: BACKGROUND
  Vinculin and its isoform metavinculin are protein components of intercalated discs, structures that anchor thin filaments and transmit contractile force between cardiac myocytes. We tested the hypothesis that heritable dysfunction of metavinculin may contribute to the pathogenesis of dilated cardiomyopathy (DCM).
  
  
  RESULTS
  We performed mutational analyses of the metavinculin-specific exon of vinculin in 350 unrelated patients with DCM. One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified. These mutations involved conserved amino acids, were absent in 500 control individuals, and significantly altered metavinculin-mediated cross-linking of actin filaments in an in vitro assay. Ultrastructural examination was performed in one patient (Arg975Trp), revealing grossly abnormal intercalated discs. A potential risk-conferring polymorphism (Ala934Val), identified in one DCM patient and one control individual, had a less pronounced effect on actin filament cross-linking.
  
  
  CONCLUSIONS
  These data provide genetic and functional evidence for vinculin as a DCM gene and suggest that metavinculin plays a critical role in cardiac structure and function. Disruption of force transmission at the thin filament-intercalated disc interface is the likely mechanism by which mutations in metavinculin may lead to DCM.
authors.affiliation: Department of Pediatrics and the Division of Cardiology, University of Utah, Salt Lake City, Utah, USA. olson.timothy@mayo.edu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.forename: Susanne
authors.initials: S
authors.lastname: Illenberger
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Kishimoto
authors.forename: Stefan
authors.initials: S
authors.lastname: Huttelmaier
authors.forename: Mark T
authors.initials: MT
authors.lastname: Keating
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Jockusch
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000648:ultrastructure; D010375:Pedigree; D016415:Sequence Alignment; D016596:Vinculin / Q000031:analogs & derivatives* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; C103334:metavinculin; D016596:Vinculin