Association of the hERG mutation with long-QT syndrome type 2, syncope and epilepsy

Li, Guoliang; Shi, Rui; Wu, Jine; Han, Wenling; Zhang, Aifeng; Cheng, Gong; Xue, Xiaolin; Sun, Changqing

doi:10.3892/mmr.2016.4859

Cited by 16 publications

(19 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whole‐cell currents were recorded in cells expressing homozygote WT‐hERG and heterozygous F463L‐hERG with and without dofetilide (1 µM) as previously described (Li et al, ). As the protocol shown in the inset, the holding potential was maintained at −90 mV, and tail currents were recorded at a level of −40 mV for 4 s after depolarizing pulses from −60 mV to +60 mV in 10 mV increments for 2 s. Representative traces were from cells expressing WT‐hERG and heterozygous F463L with and without dofetilide, respectively (Figure a).…”

Section: Resultsmentioning

confidence: 99%

F463L increases the potential of dofetilide on human ether‐a‐go‐go‐related gene (hERG) channels

Cheng

Han

et al. 2018

Microscopy Res & Technique

Self Cite

View full text Add to dashboard Cite

Mutations in genes related to long QT syndrome (LQTS) is recognized as an independent risk of drug-induced LQTS. We previously screened a mutation F463L in a Chinese patient with LQT2, syncope, and epilepsy. Here, we planned to illustrate how F463L influences the action of dofetilide on hERG channels. F463L-hERG plasmids were transfected into the stable Human Embryonic Kidney 293 (HEK293) cells expressing WT-hERG to generate heterozygous mutant (WT + F463L-hERG). Whole-cell patch clamp and laser confocal scanning microscopy were used to evaluate electrophysiological consequences and the membrane distribution of hERG protein. In comparison of WT-hERG channels exposed to dofetilide, heterozygous F463L-hERG channels showed a reduction in the density of tail currents when exposed amidarone. F463L-hERG also altered the action of dofetilide on the gating properties of hERG channels. Images of dofetilide-treated cells expressing heterozygous F463L showed a severe retention and reduction of protein expression on the membrane compared to WT. In conclusion, dofetilide displays a powerful inhibitory effect on the currents from cells expressing heterozygous F463L, thus showing an additive suppression of currents by F463L with dofetilide.

show abstract

Section: Resultsmentioning

confidence: 99%

F463L increases the potential of dofetilide on human ether‐a‐go‐go‐related gene (hERG) channels

Cheng

Han

et al. 2018

Microscopy Res & Technique

Self Cite

View full text Add to dashboard Cite

show abstract

“…The hERG channel currents were elicited by previously described voltage‐clamp protocol that is a standard protocol used to study I Kr in our laboratory (Figure 1A). 3 Briefly, the holding potential was maintained at −80 mV, and the tail currents were elicited at a level of 40 mV for 4 seconds after depolarizing pulses from −60 mV to +60 mV in 10‐mV increments for 4 seconds.…”

Section: Resultsmentioning

confidence: 99%

“…Whole‐cell patch clamp was applied to record the hERG currents as previously described 3 . Briefly, cells were incubated with 30 µmol/L posaconazole or vehicle for 48 hours.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological corrections of the mutant hERG channels by posaconazole

Luo

Zheng

et al. 2021

Clin Exp Pharma Physio

View full text Add to dashboard Cite

Properties of mutant human ether‐à‐go‐go‐related gene (hERG) channels can be modified by some antibiotics. However, the pharmacological effects of posaconazole on cardiomyocyte hERG channels remain unclear. Whole‐cell patch clamping, western blotting and laser confocal scanning microscopy were used to evaluate the effects of posaconazole on wild‐type (WT)‐, A561V‐ and L539 fs/47‐hERG channels expressed in human embryonic kidney (HEK) 293 cells. In electrophysiological experiments, HEK 293 cells were transiently co‐transfected with equal amounts of WT‐hERG, WT+A561 V‐hERG and WT+L539 fs/47‐hERG plasmids to mimic a heterozygous genotype. Posaconazole (30 μM) increased tail currents in cells expressing WT‐hERG, WT+A561 V‐hERG and WT+L539 fs/47‐hERG by 82.65%, 147.72% and 134.73%, respectively, compared to controls. Posaconazole increased hERG protein expression in cells expressing WT‐hERG, WT+A561 V‐hERG and WT+L539 fs/47‐hERG compared to controls condition as well as their trafficking to the cell membrane. To our knowledge, this is the first study to show that antifungal agent posaconazole rescues the mutant A561 V‐hERG and L539 fs/47‐hERG channels by altering the gating kinetics, enhancing the expression and trafficking of hERG channels. The results demonstrate that posaconazole could be a promising candidate for the prevention and treatment of long QT syndrome and other arrhythmia‐related diseases.

show abstract

“…Long QT syndrome (LQTs) is an inherited cardiac arrhythmia syndrome that is associated with syncope and sudden death (1-3). It has been shown that mutations exist in 15 genes encoding either ion channels or structural proteins associated with LQTs (4-7).…”

Section: Introductionmentioning

confidence: 99%

Stop codons and the +4 nucleotide may influence the efficiency of G418 in rescuing nonsense mutations of the HERG gene

Meng

Zhang

et al. 2019

Int J Mol Med

View full text Add to dashboard Cite

The importance of the local sequence context in determining how efficiently aminoglycosides rescue nonsense mutations has been established previously in disease models. Different stop codons appear to facilitate the termination process with differing efficiencies. Furthermore, the efficiency with which termination is suppressed may also be influenced by the local sequence context surrounding the stop codon. The strongest bias has usually been identified with the nucleotide base that immediately follows the stop codon in the majority of experiments. However, how the sequence context influences the efficiency of aminoglycosides in rescuing the human ether-a-go-go-related (HERG) protein in mammalian cells remains to be fully elucidated. Therefore, the present study was devised to examine the susceptibility of different termination codons on the HERG gene and the +4 nucleotide immediately following them to be suppressed by aminoglyco-sides in 293 cells. The 293 cells were transiently transfected with the wild-type or mutant genes. The read-through effect was subsequently examined by adding aminoglycoside G418 into the culture medium, followed by incubation of the cells for 24 h. An immunofluorescence method was then used to observe the protein expression of HERG prior to and following drug treatment. Patch clamping was performed to evaluate the function of the HERG protein. These experiments revealed that stop codons TGA and TAA in the R1014X mutant were more susceptible to treatment with the drug G418. Similar results were observed with the W927X-TGA and W927X-TAA mutants. Subsequently, R1014X-TGAC, R1014X-TGAG and R1014X-TGAA mutants were constructed based on the R1014X-TGAT mutant. The level of red fluorescence was observed prior to and following the administration of G418 using antibodies targeting the N- or C-terminus of the HERG protein. However, the tail current density was found only to increase with the R1014X-TGAT mutant following G418 treatment. Taken together, the results of the present study suggest that the type of premature stop codon and the context of the nucleotide immediately following at the +4 position, may determine the pharmacological rescue efficiency of the HERG gene.

show abstract

Association of the hERG mutation with long-QT syndrome type 2, syncope and epilepsy

Cited by 16 publications

References 33 publications

F463L increases the potential of dofetilide on human ether‐a‐go‐go‐related gene (hERG) channels

F463L increases the potential of dofetilide on human ether‐a‐go‐go‐related gene (hERG) channels

Pharmacological corrections of the mutant hERG channels by posaconazole

Stop codons and the +4 nucleotide may influence the efficiency of G418 in rescuing nonsense mutations of the HERG gene

Contact Info

Product

Resources

About