Vinculin and Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and systolic dysfunction, leading to heart failure and arrhythmias. Variants in VCL, encoding the cytoskeletal adaptor protein vinculin, have been implicated in the pathogenesis of DCM through both genetic and functional studies.

Genetic case–control analysis of >18,000 individuals identified 32 probands harboring heterozygous VCL loss-of-function variants, with significant enrichment in DCM patients (odds ratio = 9.01) (PMID:32516855). These LoF variants include splice-site and nonsense changes (e.g., c.2005C>T (p.Arg669Ter)). Additional targeted sequencing in DCM cohorts uncovered multiple missense variants absent in controls, indicating a spectrum of pathogenic VCL alleles.

Family studies demonstrate that heterozygous VCL LoF variants alone exhibit incomplete penetrance, but combinatorial interactions with other sarcomeric gene variants, such as TPM1, cosegregate with DCM in a large pedigree study (PMID:30923642). This suggests a contributory role for VCL in compound heterozygous or oligogenic contexts.

Functional assays of metavinculin, the muscle-specific VCL isoform, reveal that the Arg975Trp and Leu955del mutations alter actin-filament cross-linking, disrupt intercalated disc ultrastructure, and impair force transmission in vitro (PMID:11815424). Genome-edited human cardiomyocytes and knock-in mouse models carrying human VCL variants exhibit reduced contractility and sarcomere disorganization, recapitulating DCM phenotypes.

Mechanistically, pathogenic VCL variants destabilize head-tail autoinhibition, impair F-actin bundling, and weaken focal adhesions, leading to compromised cardiomyocyte mechanical integrity. Rescue of actin-binding deficits restores cytoskeletal architecture and contractile function in cellular models, confirming a haploinsufficiency and structural dysfunction mechanism.

Collectively, the genetic enrichment of VCL LoF and missense variants in DCM patients, coupled with concordant in vitro and in vivo functional defects, supports a strong gene–disease association. VCL variants should be included in diagnostic gene panels for DCM, with careful interpretation of penetrance and potential modifier interactions.

Key Take-home: Heterozygous VCL variants contribute to DCM through impaired actin binding and sarcomere stability, warranting their inclusion in clinical genetic testing for risk stratification.

References

• Nature Biomedical Engineering • 2019 • Combinatorial interactions of genetic variants in human cardiomyopathy PMID:30923642
• Human Mutation • 2020 • An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy PMID:32516855
• Circulation • 2002 • Metavinculin mutations alter actin interaction in dilated cardiomyopathy PMID:11815424

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