doi: 10.1161/hc0402.102930
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(Circulation. 2002;105:431.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Metavinculin Mutations Alter Actin Interaction in Dilated Cardiomyopathy
From the Department of Pediatrics and the Division of Cardiology (T.M.O., N.Y.K.) and the Departments of Human Genetics and Medicine, Division of Cardiology, and Howard Hughes Medical Institute (M.T.K.), University of Utah, Salt Lake City, Utah; and Cell Biology, Zoological Institute (S.I., S.H., B.M.J.), Technical University of Braunschweig, Braunschweig, Germany. Dr Keating currently is at the Department of Cell Biology, Harvard Medical School and the Department of Cardiology, Children’s Hospital, Boston, Mass.
Correspondence to Timothy M. Olson, MD, Depts of Medicine and Pediatrics, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail olson.timothy{at}mayo.edu) or Susanne Illenberger, PhD, Subdivision of Cell Biology, Zoological Institute, Technical University of Braunschweig, Spielmannstr. 7, 38106 Braunschweig, Germany (e-mail S.Illenberger@tu-bs.de).
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).
Methods and 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.
Key Words: cardiomyopathy • genetics • molecular biology
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