Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG)

Paavonen, Kristian; Chapman, Hugh; Laitinen, Päivi; Fodstad, Heidi; Piippo, Kirsi; Swan, Heikki; Toivonen, Lauri; Viitasalo, Matti; Kontula, Kimmo; Pasternack, Michael

doi:10.1016/s0008-6363(03)00458-9

Cited by 70 publications

(69 citation statements)

References 41 publications

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“…When expressed in human embryonic kidney-293 cells, Lys897Thr channels have reduced current density caused by reduced channel expression (34). When patients with the KCNH2 Lys897Thr polymorphism underwent stress testing, their QTc intervals were longer than those of controls (34). Similar observations were made in a study of Finnish women with the KCNH2 Lys897Thr polymorphism (35).…”

Section: Predictors Of Tdp and An Underlying Genetic Mutation Or Polsupporting

confidence: 55%

“…The KCNH2 Lys897Thr polymorphism in patient 4 has a population frequency of 6% to 30% (33). When expressed in human embryonic kidney-293 cells, Lys897Thr channels have reduced current density caused by reduced channel expression (34). When patients with the KCNH2 Lys897Thr polymorphism underwent stress testing, their QTc intervals were longer than those of controls (34).…”

Section: Predictors Of Tdp and An Underlying Genetic Mutation Or Polmentioning

confidence: 99%

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Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Subbiah

Gollob

Gula

et al. 2010

Canadian Journal of Cardiology

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V entricular arrhythmias have been reported in the setting of complete atrioventricular (AV) block since 1918 (1). In 1966, Dessertenne (2) described such an arrhythmia as torsades de pointes (TdP), a polymorphic ventricular tachycardia preceded by QT interval prolongation, now known to be caused by congenital or acquired long QT syndrome (LQTS) (3).Bradyarrhythmias caused by high-grade AV block are common. It is, however, infrequent that bradyarrhythmias are associated with QT interval prolongation and TdP phenomena (4-6). In patients with bradycardia-induced TdP, a number of electrocardiogram (ECG) parameters during bradycardia correlate with increased risk of TdP, including the QT interval (4-6), T wave morphology and T peak to T end (T p -T e ) (6). Although ECG parameters can be reasonable predictors of TdP in bradyarrhythmias (4-6), there are limited data on cellular or genetic mechanisms of bradycardia-induced TdP (7,8).We hypothesized that patients with bradycardia-mediated QT arrhythmia may have latent congenital LQTS or a vulnerable genetic polymorphism. In the setting of AV block, reduced repolarization reserve may be 'unmasked' in patients, manifesting as QT interval prolongation and TdP. Such an occult form of LQTS has previously been reported among patients with undiagnosed congenital LQTS who develop marked QT interval prolongation and TdP when exposed to QT-prolonging drugs (9,10). Moreover, the development of TdP in the setting of AV block may identify ion channel mutations that have a propensity to cause TdP and sudden cardiac death. INtRodUCtIoN: Atrioventricular (AV) block is infrequently associated with QT prolongation and torsades de pointes (TdP). It was hypothesized that patients with AV block-mediated QT-related arrhythmia may have latent congenital long QT syndrome or a vulnerable genetic polymorphism. Methods: Eleven patients with complete AV block and TdP were prospectively identified. Patients underwent assessment, resting electrocardiography and telemetry at baseline, during AV block and pre-TdP. Genetic testing of KCNH2, KCNQ1, KCNE1, KCNE2 and SCN5A was performed. Thirty-three patients with AV block without TdP were included for comparison. ResULts: Genetic variants were identified in 36% of patients with AV block and TdP. Patients with AV block who developed TdP had significantly longer mean (± SD) corrected QT intervals (440±93 ms versus 376±40 ms, P=0.048) and T peak to T end (T p -T e ) intervals (147±25 ms versus 94±25 ms, P=0.0001) than patients with AV block alone. In patients with a genetic variant, there was a significant increase in T p -T e intervals at baseline, in AV block and pre-TdP compared with those who were genotype negative. A personal or family history of syncope or sudden death was more likely observed in patients with a genetic variant. CoNCLUsIoNs: TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. The T p -T e interval at baseline, in AV block and pre-TdP may predict a genetic mutation ...

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Section: Predictors Of Tdp and An Underlying Genetic Mutation Or Polsupporting

confidence: 55%

Section: Predictors Of Tdp and An Underlying Genetic Mutation Or Polmentioning

confidence: 99%

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Subbiah

Gollob

Gula

et al. 2010

Canadian Journal of Cardiology

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“…Whole-cell patch-clamp recordings were performed using an EPC-9 amplifier and Pulse/Pulsefit software (Heka, Lambrecht, Germany) as described previously (Paavonen et al, 2003). The electrodes had resistances of 2-4 M⍀ when filled with 150 mM KCl, 2 mM MgCl 2 , 5 mM BAPTA, 5 mM Mg 2 ATP 3 and 10 mM HEPES, pH 7.2.…”

Section: Patch-clamp Recordingmentioning

confidence: 99%

Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation

Chapman

Ramström

Korhonen

et al. 2005

Journal of Cell Science

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The HERG (KCNH2) potassium channel underlies the rapid component of the delayed rectifier current (Ikr), a current contributing to the repolarisation of the cardiac action potential. Mutations in HERG can cause the hereditary forms of the short-QT and long-QT syndromes, predisposing to ventricular arrhythmias and sudden cardiac death. HERG is expressed mainly in the cell membrane of cardiac myocytes, but has also been identified in cell membranes of a range of other cells, including smooth muscle and neurones. The mechanisms regulating the surface expression have however not yet been elucidated. Here we show, using stable HERG-expressing HEK 293 cells, that ceramide evokes a time-dependent decrease in HERG current which was not attributable to a change in gating properties of the channel. Surface expression of the HERG channel protein was reduced by ceramide as shown by biotinylation of surface proteins, western blotting and immunocytochemistry. The rapid decline in HERG protein after ceramide stimulation was due to protein ubiquitylation and its association with lysosomes. The results demonstrate that the surface expression of HERG is strictly regulated, and that ceramide modifies HERG currents and targets the protein for lysosomal degradation.

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“…The distinct properties of iPSC-CMs derived from the proband compared with those derived from the parents reinforce the utility of these cells in detecting patient-specific channel defects and hence improve potential approaches to manage dysfunctional channel activity. Studies in the iPSC-CMs eliminated a role of the common K897T polymorphism in the response of the patient to anti-arrhythmic drug therapies, a particularly important finding because heterologous expression studies have reported differing effects of this variant on channel activity (Bezzina et al, 2003;Paavonen et al, 2003;Anson et al, 2004;Crotti et al, 2005;Rhodes et al, 2008;Sinner et al, 2008). impact of adding a second Na + channel blocker, flecainide, two clinical options frequently used empirically to treat LQTS-3.…”

Section: Discussionmentioning

confidence: 99%

“…Heterologous expression of mutant Na + channels in mammalian (HEK293) cells identified a severe defect in inactivation and illustrated the utility of Na + channel blockers to correct the mutation-induced channel dysfunction (Bankston et al, 2007b). The contribution of the KCNH2 polymorphism to the disease phenotype and pro-and anti-arrhythmic drug effects was unknown despite studies suggesting a causal link between this polymorphism and arrhythmia (Bezzina et al, 2003;Paavonen et al, 2003;Anson et al, 2004;Crotti et al, 2005;Rhodes et al, 2008;Sinner et al, 2008). At the start of the present study, the patient was 4 yr old and was maintained on 24 mg/kg/d mexiletine stem cells (hESCs) derived using the same procedures ( Fig.…”

Section: Na + Channel Activity In Ipsc-cmsmentioning

confidence: 99%

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

Terrenoire¹,

Wang²,

Tung³

et al. 2013

J Cell Biol

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Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG)

Abstract: The K897T variation has an effect on channel function and clinical phenotype. Our data warrant further investigations into the significance of this polymorphism in drug-induced and inherited LQTS.

Cited by 70 publications

References 41 publications

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

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