title: Association of the hERG mutation with long-QT syndrome type 2, syncope and epilepsy.
abstract: Mutations in the human ether‑à‑go‑go‑related gene (hERG) are responsible for long‑QT syndrome (LQTS) type 2 (LQT2). In the present study, a heterozygous missense mutation (A561V) linked to LQT2, syncope and epilepsy was identified in the S5/pore region of the hERG protein. The mutation, A561V, was prepared and subcloned into hERG‑pcDNA3.0. Mutant plasmids were co‑transfected into HEK‑293 cells, which stably express wild‑type (WT) hERG, in order to mimic a heterozygous genotype, and the whole‑cell current was recorded using a patch‑clamp technique. Confocal microscopy was performed to evaluate the membrane distribution of the hERG channel protein using a green fluorescent protein tagged to the N‑terminus of hERG. A561V‑hERG decreased the amplitude of the WT‑hERG currents in a concentration‑dependent manner. In addition, A561V‑hERG resulted in alterations to activation, inactivation and recovery from inactivation in the hERG protein channels. Further evaluation of hERG membrane localization indicated that the A561V‑hERG mutant protein was unable to travel to the plasma membrane, which resulted in a trafficking‑deficient WT‑hERG protein. In conclusion, A561V‑hERG exerts a potent dominant‑negative effect on WT‑hERG channels, resulting in decreased hERG currents and impairment of hERG membrane localization. This may partially elucidate the clinical manifestations of LQTS patients who carry the A561V mutation.
authors: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
authors: Guoliang
authors: G
authors: Li
authors: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
authors: Rui
authors: R
authors: Shi
authors: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
authors: Jine
authors: J
authors: Wu
authors: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
authors: Wenqi
authors: W
authors: Han
authors: Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710004, P.R. China.
authors: Aifeng
authors: A
authors: Zhang
authors: Department of Cardiovascular Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Gong
authors: G
authors: Cheng
authors: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
authors: Xiaolin
authors: X
authors: Xue
authors: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China.
authors: Chaofeng
authors: C
authors: Sun
mesh_terms: D000293:Adolescent; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D020125:Mutation, Missense; D021381:Protein Transport; D013575:Syncope / Q000235:genetics*
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human