ACTC1 – Dilated Cardiomyopathy

Autosomal dominant dilated cardiomyopathy (DCM) has been linked to heterozygous missense mutations in the cardiac α-actin gene ACTC1. A genome-wide linkage study in a 78-member kindred mapped DCM and atrial septal defects to chromosome 15q14, identifying a fully penetrant ACTC1 c.740G>A (p.Gly247Asp) variant in 15 affected individuals and absent in 63 unaffected relatives (PMID:31430208).

Segregation analysis confirmed co-segregation of the variant in a multi-generational family with 15 affected carriers and no healthy carriers, supporting autosomal dominant inheritance and high penetrance (PMID:31430208). In silico tools predicted deleterious effects, and the variant is absent from control databases, indicating it is not a benign polymorphism.

Histopathology of myocardial tissue from a mutation carrier revealed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis. Proteomic profiling showed upregulation of extracellular matrix proteins, consistent with remodeling seen in DCM (PMID:31430208).

Neonatal rat ventricular cardiomyocytes overexpressing the p.Gly247Asp mutant exhibited structural defects and increased apoptosis compared to cells expressing WT ACTC1. Molecular dynamics and actin polymerization assays confirmed that the mutation impairs filament assembly and turnover (PMID:31430208).

Further functional assays demonstrated that G247D-ACTC1 abolishes serum response factor (SRF)-mediated transcriptional activation due to disrupted Rho-GTPase signaling and increased nuclear G-actin, providing a mechanistic link to impaired cardiomyocyte gene expression and late-onset DCM (PMID:31434612).

Negative screening studies in Japanese and Finnish cohorts found no pathogenic ACTC1 variants in sporadic DCM, underscoring the rarity and high penetrance of the p.Gly247Asp mutation but not refuting the association in familial cases.

Detection of ACTC1 mutations in patients with ASD or early DCM enables pre-symptomatic family screening, risk stratification, and timely intervention. Key take-home: ACTC1 c.740G>A (p.Gly247Asp) is a pathogenic, autosomal dominant variant causing DCM by disrupting actin polymerization and SRF signaling.

References

• Circulation. Genomic and precision medicine • 2019 • Cardiac α-Actin (ACTC1) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy PMID:31430208
• Biochemical and biophysical research communications • 2019 • A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocyte PMID:31434612

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