Cardiac α-Actin ( ACTC1 ) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy

Abstract

Background: Familial atrial septal defect (ASD) has previously been attributed primarily to mutations in cardiac transcription factors. Here, we report a large, multi-generational family (78 members) with ASD combined with a late-onset dilated cardiomyopathy and further characterize the consequences of mutant α-actin. Methods: We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac α-actin) mutation identified in association with ASD and late-onset dilated cardiomyopathy in a large, multi-generational family. Results: Using a genome-wide linkage analysis, the ASD disease locus was mapped to chromosome 15q14 harboring the ACTC1 gene. In 15 affected family members, a heterozygous, nonsynonymous, and fully penetrant mutation (p. Gly247Asp) was identified in exon 5 of ACTC1 that was absent in all healthy family members (n=63). In silico tools predicted deleterious consequences of this variant that was found absent in control databases. Ultrastructural analysis of myocardial tissue of one of the mutation carriers showed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis, while cardiac proteomics revealed a significant increase in extracellular matrix proteins. Consistently, structural defects and increased apoptosis were also observed in neonatal rat ventricular cardiomyocytes overexpressing the mutant, but not native human ACTC1. Molecular dynamics studies and additional mechanistic analyses in cardiomyocytes confirmed actin polymerization/turnover defects, thereby affecting contractility. Conclusions: A combined phenotype of ASD and late-onset heart failure was caused by a heterozygous, nonsynonymous ACTC1 mutation. Mechanistically, we found a shared molecular mechanism of defective actin signaling and polymerization in both cardiac development and contractile function. Detection of ACTC1 mutations in patients with ASD may thus have further clinical implications with regard to monitoring for (late-onset) dilated cardiomyopathy.

Fibulin-3 Deficiency Protects Against Myocardial Injury Following Ischaemia/ Reperfusion in in vitro Cardiac Spheroids

“…We found that Actc1 was downregulated in both WT and Fib-3 KO I/R CSs compared to their respective controls. Actc1 mutation was previously reported to upregulate Fib-3 upregulation, supporting a potential correlation between Fib-3 deficiency and sarcomeric proteins regulating contractile function ( 28 ). With respect to calcium ion transport genes, we found a significant increase in relative expression of Atp5a1 in Fib-3 KO I/R CSs compared to WT I/R CSs, which may play a role in regulating contractile function and response to I/R injury.…”

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway

“…DCM-associated BAG3 mutations impaired Z-disc assembly and increased the stress-induced apoptosis in cultured cardiomyocytes [22,23]. And cardiac tissue from a DCM patient harboring a nonsynonymous mutation in α-actin gene also displayed sarcomeric disarray, and an increase in cardiomyocytes apoptosis [24].…”

Myocardial Injury Caused by Chronic Alcohol Exposure—A Pilot Study Based on Proteomics

“…Mazzarotto et al demonstrated that variants of TPM 1 and Actc 1 were found to be significantly enriched in selected DCM patients through clinical studies [48]. Detection of Actc 1 mutations has clinical implications for monitoring delayed DCM [49]. Therefore, TPM 1 and Actc 1 may be involved in the process of DCM induced by alcohol exposure, but the specific mechanism still needs to be further studied.…”