Partial expression defect for the <i>SCN5A</i> missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine

Tan, Bi Hua; Valdivia, Carmen R.; Song, Chunhua; Makielski, Jonathan C.

doi:10.1152/ajpheart.00101.2006

Cited by 56 publications

(50 citation statements)

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“…Reduced sodium current is thought to exaggerate discrepancy in the action potential duration between the inner and outer layers of ventricular muscle, thereby introducing increased electrophysiological heterogeneity [23]. There are three common mechanisms that mutations in the SCN5A can lead to loss of function [8,15,24]: (1) incomplete transcription due to nonsense mutations that cause the channel protein not to be produced. (2) Channel proteins are produced but intracellular trafficking of the channel proteins is impaired thus membrane surface expression of the channel protein are decreased.…”

Section: Discussionmentioning

confidence: 99%

“…After 3–5 hours of incubation, the transfection reagent-DNA mixture was replaced with 3 ml of normal culture medium with or without 500 μM mexiletine, and the cells were incubated at 37°C for 48 hours. Before the electrophysiological recording, the plates containing the cells were removed from the 37°C incubator, growth medium was aspirated off the plates with or without drug, and the cells were treated with a 0.25% trypsin-1 mM EDTA solution (GIBCO-BRL) and transferred to a fresh tube along with 2 ml of normal culture medium and directly to the experimental chamber for electrophysiological recording [15]. …”

Section: Methodsmentioning

confidence: 99%

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Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

Channels

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Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. Methods and Results: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. Conclusion: SCN5A-N406K channel displays both “gain-of-function” in late INa and “loss-of-function” in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both “gain-of-function” and “loss-of-function” of the mutant sodium channel.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

Channels

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“…81 Other examples of beneficial drug effects include reports suggesting that quinidine may ameliorate the ECG phenotype and arrhythmic risk of patients with Brugada syndrome via quinidine-induced I to blockade 82,83 and may effectively treat (by I Kr blockade) the gain-of-function mutation in I Kr associated with 1 form of the congenital short-QT syndrome, 84 as well as the use of mexiletine or flecainide as a treatment for congenital LQT3. [85][86][87] …”

Section: Future Strategiesmentioning

confidence: 99%

Drug-Induced Arrhythmia

Heist

Ruskin

2010

Circulation

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“…20,38 Furthermore, in vitro experiments do not consider the important contribution to arrhythmogenesis of the signaling pathways, receptors, and autonomic modulation.…”

Section: Ruan Et Al Paradoxical Effect Of Mexiletine On Lqt3mentioning

confidence: 99%

Trafficking Defects and Gating Abnormalities of a Novel SCN5A Mutation Question Gene-Specific Therapy in Long QT Syndrome Type 3

Ruan

Denegri

Liu

et al. 2010

Circulation Research

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Rationale: Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations. Objective: We sought to investigate the unexpected deleterious effect of mexiletine in a mutation combining gain-offunction and trafficking abnormalities. Methods and Results: A long-QT syndrome type 3 child experienced paradoxical QT prolongation and worsening of arrhythmias after mexiletine treatment. The SCN5A mutation F1473S expressed in HEK293 cells presented a right-ward shift of steady-state inactivation, enlarged window current, and huge sustained sodium current. Unexpectedly, it also reduced the peak sodium current by 80%. Immunostaining showed that mutant Nav1.5 is retained in the cytoplasm. Incubation with 10 mol/L mexiletine rescued the trafficking defect of F1473S, causing a significant increase in peak current, whereas sustained current was unchanged. Using a Markovian model of the Na channel and a model of human ventricular action potential, we showed that simulated exposure of F1473S to mexiletine paradoxically increased action potential duration, mimicking QT prolongation seen in the index patient on mexiletine treatment. Conclusions: Sodium channel blockers are largely used to shorten QT intervals in carriers of SCN5A mutations. We provided evidence that these agents may facilitate trafficking of mutant proteins, thus exacerbating QT prolongation. These data suggest that caution should be used when recommending this class of drugs to carriers of mutations with undefined electrophysiological properties. (Circ Res. 2010;106:1374-1383.)Key Words: electrophysiology Ⅲ genetics Ⅲ long-QT syndrome Ⅲ pharmacology Ⅲ ion channels L ong-QT syndrome is an inherited arrhythmogenic disease characterized by QT interval prolongation and susceptibility to ventricular tachyarrhythmias. Long-QT syndrome type 3 (LQT3) is a variant of long-QT syndrome characterized by high lethality, 1 marked prolongation of repolarization, poor response to ␤-blockers, 2 and cardiac events occurring preferentially at rest. LQT3 is caused by mutations in the SCN5A gene that encode for the ␣ subunit of the channel that conducts the inward sodium current responsible for fast depolarization and critical for maintenance of intracardiac conduction. 3,4 Following the identification of the first SCN5A mutation published in 1995, 5 more than 80 SCN5A mutations have been identified in LQT3 patients.SCN5A mutations associated with LQT3 increase the sodium current by augmenting either the sustained sodium current (I sus ) or the window current, thus prolonging cardiac repolarization. 6 Based on this evidence, the use of sodium channel blockers to treat LQT3 patients and reduce QT interval has been proposed. Early in vitro studies 7 demonstrated that mexiletine is effective in shortening action potential duration (APD) in cardiac myocytes exposed to anthopleurin, a compound that mimics LQT3 cellular phenoty...

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Partial expression defect for the SCN5A missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine

Abstract: Tan, Bi-Hua, Carmen R. Valdivia, Chunhua Song, and Jonathan C. Makielski. Partial expression defect for the SCN5A missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine.

Cited by 56 publications

References 19 publications

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Drug-Induced Arrhythmia

Trafficking Defects and Gating Abnormalities of a Novel SCN5A Mutation Question Gene-Specific Therapy in Long QT Syndrome Type 3

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