title: Identification and functional characterization of the human ether-a-go-go-related gene Q738X mutant associated with hereditary long QT syndrome type 2.
abstract: QT interval prolongation, a risk factor for arrhythmias, may be associated with genetic variants in genes governing cardiac repolarization. Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go‑go-related gene (hERG). This gene encodes a voltage-gated potassium channel comprised of 4 subunits, and the formation of functional channels requires the proper assembly of these 4 subunits. In the present study, we investigated the role of the LQT2 mutation, Q738X, which causes truncation of the C-terminus of hERG channels, in the assembly and function of hERG channels. When expressed in HEK293 cells, Q738X did not generate an hERG current. The co-expression of Q738X with wild-type (WT)-hERG did not cause the dominant-negative suppression of the WT-hERG current. Western blot analysis and confocal microscopy revealed that the Q738X mutation caused defective trafficking of hERG channel proteins. Co-immunoprecipitation demonstrated that Q738X did not exhibit dominant-negative effects due to the failure of the mutant and WT subunits to co-assemble. In conclusion, the functional loss caused by the Q738X mutation in hERG K+ channels may be attributed to the disruption of tetrameric assembly.
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Sheng-Na
authors.initials: SN
authors.lastname: Han
authors.affiliation: The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Song-Hua
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Pharmacy College of Zhengzhou Railway Vocational and Technical College, Zhengzhou, Henan, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Xiang-Jie
authors.initials: XJ
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Chen-Zheng
authors.initials: CZ
authors.lastname: Huang
authors.affiliation: The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Ge
authors.initials: G
authors.lastname: Yang
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, P.R. China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, P.R. China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D014162:Transfection
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human