Sudden infant death syndrome–associated mutations in the sodium channel beta subunits

Tan, Bi Hua; Pundi, Krishna; Norstrand, David W. Van; Valdivia, Carmen R.; Tester, David J.; Medeiros-Domingo, Argelia; Makielski, Jonathan C.; Ackerman, Michael J.

doi:10.1016/j.hrthm.2010.01.032

Cited by 108 publications

(115 citation statements)

References 35 publications

(44 reference statements)

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“…Coexpression of Nav1.5 with p.V36M ␤3-subunit resulted in a decrease in peak I Na density but, interestingly, also in an increase of the persistent I Na , compared with coexpression with normal ␤3-subunits, showing that mutations in ␤3-subunits may also cause I Na gain of function. 84 Taken together, findings from these translational studies are largely in line with those obtained from in vitro experiments and SCN3B knockout mice and indicate that ␤3-subunit plays an important regulatory role in the sarcolemmal expression and gating of Na v 1.5. However, recently, Wang and colleagues sequenced 477 patients with AF for mutations in SCN3B and identified a missense mutation in SCN3B (c.389CϾT resulting in p.A130V, located in the distal portion of the amino terminus) in one patient.…”

Section: Wilde and Brugada Cardiac Disease And Subunits Of The Sodiumsupporting

confidence: 70%

“…26,83 Recently, the p.V54G mutation was also linked to SIDS. 84 Makielski and colleagues screened 292 SIDS cases for mutations in ␤-subunit-encoding genes and found a mutation in SCN3B in 2 cases (V54G, and c.106GϾA resulting in p.V36M, located in the amino terminus). Coexpression of Nav1.5 with p.V36M ␤3-subunit resulted in a decrease in peak I Na density but, interestingly, also in an increase of the persistent I Na , compared with coexpression with normal ␤3-subunits, showing that mutations in ␤3-subunits may also cause I Na gain of function.…”

Section: Wilde and Brugada Cardiac Disease And Subunits Of The Sodiummentioning

confidence: 99%

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Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Wilde

Brugada

2011

Circulation Research

189

134

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Abstract:Variations in the gene encoding for the major sodium channel (Na v 1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Of equal importance are variations in genes encoding for various subunits and regulatory proteins interacting with the ␣-subunit Na v 1.5 and modifying its function. Based on detailed studies of genotype-phenotype relationships in these disease entities, on detailed studies of the basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels and their interacting proteins), and on attempts to integrate the obtained knowledge, the past 15 years has witnessed an explosion of knowledge about these disease entities. (Circ Res. 2011;108:884-897.) Key Words: sodium channel Ⅲ arrhythmias Ⅲ sudden cardiac death I nitially based on genetic studies in the mid-1990s, the SCN5A gene, encoding the major sodium channel (Na v 1.5) in the heart, has been unmasked as an important player in a number of primary arrhythmia syndromes. Indeed, sodium channel dysfunction resulting from mutation-based alterations in channel function is associated with the long-QT syndrome (LQTS) (type 3), 1 the syndrome of right precordial ST elevation, ie, Brugada syndrome (BrS), 2 (progressive) cardiac conduction disease (CCD), 2,3 sinus node dysfunction, 4 atrial fibrillation (AF), 5 atrial standstill, 6,7 and dilated cardiomyopathy. 8 Because many of these diseases associate with sudden death in young individuals with a structurally normal heart, potentially causal SCN5A variants have also been identified in sudden infant or sudden unexplained death syndrome (SIDS/SUDS). 9,10 Detailed descriptions of the clinical (patients) and basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels) have profoundly increased our knowledge about these disease entities and about the role of the sodium channel and its interaction with various subunits. Indeed, besidesOriginal received September 2, 2010; resubmission received December 8, 2010; revised resubmission received January 13, 2011; accepted January 28, 2011. In December 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days. ␤-subunits (␤1 to ␤4), the ␣-subunit Na v 1.5 also interacts with several regulatory proteins, of which, more recently, malfunction resulting from disease-causing variants in their encoding genes has been shown to underlie comparable phenotypes. This article aims to review the existing knowledge of the basic and clinical aspects of sodium channel related diseases. It begins with a review of sodium channel function in normal and abnormal conditions that is followed by a description of the diverse clinical phenotypes. The Cardia...

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Section: Wilde and Brugada Cardiac Disease And Subunits Of The Sodiumsupporting

confidence: 70%

Section: Wilde and Brugada Cardiac Disease And Subunits Of The Sodiummentioning

confidence: 99%

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Wilde

Brugada

2011

Circulation Research

189

134

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“…patient with BrS, 23 although some other SCN3B mutations have been reported in other hereditary arrhythmias, including IVF, 27 SIDS, 28 and AF. 29, 30 We report a SCN3B mutation, Val110Ile, found in 3 unrelated Japanese BrS patients.…”

mentioning

confidence: 97%

Novel <i>SCN3B</i> Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5

Ishikawa

Takahashi

Ohno

et al. 2013

Circ J

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“…First, the incomplete inactivation resulted in an enlarged overlapping area between the steady-state activation and inactivation curves, thereby increased the window current of combined mutant channel. The window current is primarily determined by the overlap of sodium channel activation and inactivation (16,26). It identifies a range of voltages where channels have a small probability of being partially but not fully inactivated (6).…”

Section: Discussionmentioning

confidence: 99%

Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I_Na contributing to LQT syndrome

Tan

Orland

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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are reported susceptible genes for long QT syndrome (LQTS). This study was designed to elucidate a plausible pathogenic arrhythmia mechanism for the combined novel mutations R800L-SCN5A and A261V-SNTA1 on cardiac sodium channels. A Caucasian family with syncope and marginally prolonged QT interval was screened for LQTS-susceptibility genes and found to harbor the R800L mutation in SCN5A and A261V mutation in SNTA1, and those with both mutations had the strongest clinical phenotype. The mutations were engineered into the most common splice variant of human SCN5A and SNTA1 cDNA, respectively, and sodium current (INa) was characterized in human embryonic kidney 293 cells cotransfected with neuronal nitric oxide synthase (nNOS) and the cardiac isoform of the plasma membrane Ca-ATPase (PMCA4b). Peak INa densities were unchanged for wild-type (WT) and for mutant channels containing R800L-SCN5A, A261V-SNTA1, or R800L-SCN5A plus A261V-SNTA1. However, late INa for either single mutant was moderately increased two-to threefold compared with WT. The combined mutations of R800L-SCN5A plus A261V-SNTA1 significantly enhanced the I Na late/peak ratio by 5.6-fold compared with WT. The time constants of current decay of combined mutant channel were markedly increased. The gain-of-function effect could be blocked by the N G -monomethyl-L-arginine, a nNOS inhibitor. We conclude that novel mutations in SCN5A and SNTA1 jointly exert a nNOS-dependent gain-of-function on SCN5A channels, which may consequently prolong the action potential duration and lead to LQTS phenotype.

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Sudden infant death syndrome–associated mutations in the sodium channel beta subunits

Cited by 108 publications

References 35 publications

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Novel <i>SCN3B</i> Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5

Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I_Na contributing to LQT syndrome

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Sudden infant death syndrome–associated mutations in the sodium channel beta subunits

Cited by 108 publications

References 35 publications

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Novel <i>SCN3B</i> Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5

Digenic inheritance novel mutations in SCN5a and SNTA1 increase late INa contributing to LQT syndrome

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Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I_Na contributing to LQT syndrome