A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes

Biochem Biophys Res Commun. 2019 Oct 20;518(3):500-505. doi: 10.1016/j.bbrc.2019.08.081. Epub 2019 Aug 18.


We recently identified a novel, heterozygous, and non-synonymous ACTC1 mutation (p.Gly247Asp or G247D) in a large, multi-generational family, causing atrial-septal defect followed by late-onset dilated cardiomyopathy (DCM). Molecular dynamics studies revealed possible actin polymerization defects as G247D mutation resides at the juncture of side-chain interaction, which was indeed confirmed by in vitro actin polymerization assays. Since polymerization/de-polymerization is important for the activation of Rho-GTPase-mediated serum response factor (SRF)-signaling, we studied the effect of G247D mutation using luciferase assay. Overexpression of native human ACTC1 in neonatal rat cardiomyocytes (NRVCMs) strongly activated SRF-signaling both in C2C12 cells and NRVCMs, whereas, G247D mutation abolished this activation. Mechanistically, we found reduced GTP-bound Rho-GTPase and increased nuclear localization of globular actin in NRVCMs overexpressing mutant ACTC1 possibly causing inhibition of SRF-signaling activation. In conclusion, our data suggests that human G247D ACTC1 mutation negatively regulates SRF-signaling likely contributing to the late-onset DCM observed in mutation carrier patients.

Keywords: ACTC1; Atrial-septal defect; Dilated cardiomyopathy; Rho-GTPase; Serum response factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics*
  • Actins / metabolism
  • Animals
  • Animals, Newborn
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / metabolism
  • Cardiomyopathy, Dilated / pathology
  • Cell Line
  • Cells, Cultured
  • Humans
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Point Mutation*
  • Rats
  • Signal Transduction
  • Transcription Factors / metabolism*


  • ACTC1 protein, human
  • Actins
  • Transcription Factors
  • serum response factor, rat