A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.

Autor: Cheng YJ; Department of Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China., Wu Y; Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.; NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China., Wei HQ; Department of Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China., Liao YJ; The First Clinical Medical College, Guangdong Medical University, Zhanjiang, China., Qu LP; Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.; NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China., Pan YH; Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.; NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China., Liu LJ; Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. liulj35@mail.sysu.edu.cn.; NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China. liulj35@mail.sysu.edu.cn., Bi WT; Department of Cardiovascular Medicine, People's Hospital of Macheng City, Macheng, China. biwt3@mail2.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Molecular biology reports [Mol Biol Rep] 2024 Apr 16; Vol. 51 (1), pp. 520. Date of Electronic Publication: 2024 Apr 16.
DOI: 10.1007/s11033-024-09421-9
Abstrakt: Background: Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive.
Methods: A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques.
Results: The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics.
Conclusions: These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.
(© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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