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.