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Metavinculin mutations alter actin interaction in dilated cardiomyopathy
Timothy M Olson1, Susanne Illenberger, Nina Y Kishimoto
1Department of Pediatrics and the Division of Cardiology, University of Utah, Salt Lake City, Utah, USA. olson.timothy@mayo.edu
Circulation
|January 30, 2002
Summary
Heritable metavinculin dysfunction, a protein in cardiac intercalated discs, may cause dilated cardiomyopathy (DCM). Genetic and functional studies identified mutations disrupting actin filament cross-linking, suggesting a role in DCM pathogenesis.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
Background:
- Vinculin and its isoform metavinculin are key proteins in cardiac intercalated discs, essential for anchoring and force transmission.
- Intercalated discs connect cardiac myocytes, ensuring coordinated heart contractions.
Purpose of the Study:
- To investigate the hypothesis that heritable metavinculin dysfunction contributes to the development of dilated cardiomyopathy (DCM).
Main Methods:
- Conducted mutational analyses of the metavinculin-specific exon in 350 DCM patients and 500 controls.
- Performed in vitro assays to assess the functional impact of identified mutations on actin filament cross-linking.
- Conducted ultrastructural examination of intercalated discs in a patient with a specific mutation.
Main Results:
- Identified two mutations (Arg975Trp, Leu954del) in conserved amino acids, absent in controls, significantly altering metavinculin function.
- Observed grossly abnormal intercalated discs in a patient with the Arg975Trp mutation.
- A polymorphism (Ala934Val) showed a less significant effect on actin filament cross-linking.
Conclusions:
- Provided genetic and functional evidence implicating vinculin, specifically metavinculin, as a DCM-associated gene.
- Disruption of force transmission at the intercalated disc interface is proposed as the mechanism leading to DCM.
- Metavinculin plays a critical role in maintaining cardiac structure and function.
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