关键词: ACTC1 Atrial-septal defect Dilated cardiomyopathy Rho-GTPase Serum response factor

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

来  源:   DOI:10.1016/j.bbrc.2019.08.081   PDF(Sci-hub)

Abstract:
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.
摘要:
暂无翻译
公众号