Escape capture bigeminy: Phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q

Nair, Kalyani; Pekhletski, Roman; Harris, Louise; Care, Melanie; Morel, Chantal F.; Farid, Talha; Backx, Peter H.; Szabó, Elöd Z.; Nanthakumar, Kumaraswamy

doi:10.1016/j.hrthm.2012.06.029

Cited by 50 publications

(55 citation statements)

References 23 publications

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“…[2][3][4] In the current study, the clinical phenotype, associating with the p.I141V mutation, was characterized by a distinct hyperexcitability without evidence of conduction abnormalities or QT interval prolongation. Although the p.I141V and the p.R222Q mutation both associate with atrial arrhythmias, the clinical characteristics of the individuals carrying the p.I141V mutation differ from the phenotype described in p.R222Q-carriers.…”

Section: Gain-of-function Mutations In Na V 15 and The Clinical Phenmentioning

confidence: 66%

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Swan

Amarouch

Leinonen

et al. 2014

Circ Cardiovasc Genet

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Background-Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family. Methods and Results-A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Na v 1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells. Conclusions-Gain

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Section: Gain-of-function Mutations In Na V 15 and The Clinical Phenmentioning

confidence: 66%

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Swan

Amarouch

Leinonen

et al. 2014

Circ Cardiovasc Genet

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show abstract

“…5 A similar functional defect was subsequently observed for the D1/S4 mutation R222Q, which had been identified independently by four groups. The phenotype associated with R222Q was described variably as peripartum dilated cardiomyopathy, 6,19 arrhythmic dilated cardiomyopathy, 9 escape capture bigeminy and cardiomyopathy, 10 reversible ventricular ectopy and dilated cardiomyopathy or multifocal ectopic Purkinje-related premature contractions. 7 Most of these reports emphasized the high burden of ectopic premature ventricular beats and impaired cardiac contractility with the variable presence of atrial tachyarrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy

et al. 2014

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Background Mutations in SCN5A, encoding the cardiac sodium channel (NaV1.5) typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia. Here we present the clinical, genetic and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain. Methods and results A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P expressed heterologously in tsA201 cells. Mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window- and ramp-currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long-QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current and enhanced frequency-dependent rundown of channel availability. Conclusion We determined the functional consequences and pharmacological responses of a novel SCN5A mutation associated with an arrhythmia-associated cardiomyopathy. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation as a shared molecular mechanism of the syndrome.

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“…16 Thus, SCN5A mutations in each S4 segment and even those in the same S4 segment may cause diverse functional abnormalities and phenotypic manifestations. 6,8,[17][18][19][20][21][22][23] It has been reported that recovery from fast inactivation of I Na may be associated with immobilized gating charge caused by the slow movement of the S4 segments in domains III and IV, but not in domains I and II, 15 which suggested that recovery from fast inactivation of I Na would be impaired by R1632C mutation.…”

Section: Introductionmentioning

confidence: 99%

Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome

et al. 2015

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Escape capture bigeminy: Phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q

Cited by 50 publications

References 23 publications

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy

Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome

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