α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Cheng, Jianding; Norstrand, David W. Van; Medeiros-Domingo, Argelia; Valdivia, Carmen R.; Tan, Bi-Hua; Ye, Bin; Kroboth, Stacie; Vatta, Matteo; Tester, David J.; January, Craig T.; Makielski, Jonathan C.; Ackerman, Michael J.

doi:10.1161/circep.109.891440

Cited by 85 publications

(75 citation statements)

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“…The exact molecular mechanisms underlying the loss of Na v 1.5 expression at the lateral membrane in the absence of dystrophin remains still unclear. Cheng and coworkers 33 recently described several mutations in the gene encoding ␣1-syntrophin in patients with sudden infant death syndrome. Despite these results, clearly demonstrating the importance of ␣1-syntrophin in cardiomyocytes function, our data suggest that this protein complex is restricted to the lateral membrane.…”

Section: Physiological Relevance Of the Two Regulating Mechanismsmentioning

confidence: 99%

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Petitprez

Zmoos

Ogrodnik³

et al. 2011

Circulation Research

244

237

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Rationale:The cardiac sodium channel Na v 1.5 plays a key role in excitability and conduction. The 3 last residues of Na v 1.5 (Ser-Ile-Val) constitute a PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at the intercalated discs, Na v 1.5 could potentially interact with other, yet unknown, proteins at this site.Objective: The aim of this study was to determine whether Na v 1.5 is part of distinct regulatory complexes at lateral membranes and intercalated discs. Methods and Results:Immunostaining experiments demonstrated that Na v 1.5 localizes at lateral membranes of cardiomyocytes with dystrophin and syntrophin. Optical measurements on isolated dystrophin-deficient mdx hearts revealed significantly reduced conduction velocity, accompanied by strong reduction of Na v 1.5 at lateral membranes of mdx cardiomyocytes. Pull-down experiments revealed that the MAGUK protein SAP97 also interacts with the SIV motif of Na v 1.5, an interaction specific for SAP97 as no pull-down could be detected with other cardiac MAGUK proteins (PSD95 or ZO-1). Furthermore, immunostainings showed that Na v 1.5 and SAP97 are both localized at intercalated discs. Silencing of SAP97 expression in HEK293 and rat cardiomyocytes resulted in reduced sodium current (I Na ) measured by patch-clamp. The I Na generated by Na v 1.5 channels lacking the SIV motif was also reduced. Finally, surface expression of Na v 1.5 was decreased in silenced cells, as well as in cells transfected with SIV-truncated channels. Conclusions:These data support a model with at least 2 coexisting pools of Na v 1.5 channels in cardiomyocytes: one targeted at lateral membranes by the syntrophin-dystrophin complex, and one at intercalated discs by SAP97. (Circ Res. 2011;108:294-304.) Key Words: sodium channel Ⅲ Na v 1.5 Ⅲ MAGUK proteins Ⅲ SAP97 Ⅲ dystrophin T he cardiac sodium channel Na v 1.5 initiates the cardiac action potential, thus playing a key role in cardiac excitability and impulse propagation. The physiological importance of this channel is illustrated by numerous cardiac pathologies caused by hundreds of mutations identified in SCN5A, the gene encoding Na v 1.5. 1 The Na v 1.5 channel is composed of one 220-kDa ␣-subunit that constitutes a functional channel, and 30-kDa ␤-subunits. In addition to these accessory ␤-subunits, several proteins have been shown to regulate and interact with Na v 1.5. 1,2 In most cases, the physiological relevance of these interactions is poorly understood, mainly because of a lack of appropriate animal models. Many of the interacting proteins bind to the C terminus of Na v 1.5, where several protein-protein interaction motifs are located. 1,2 We have shown that the ubiquitin-protein ligase Nedd4-2 binds the PY motif of Na v 1.5 and reduces the sodium current (I Na ) in HEK293 cells by promoting its internalization. 3 We have also demonstrated that Na v 1.5 associates with the dystrophin-syntrophin multiprotein complex (DMC) in cardiac cells. 4 In dystrophin-deficient mice (m...

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Section: Physiological Relevance Of the Two Regulating Mechanismsmentioning

confidence: 99%

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Petitprez

Zmoos

Ogrodnik³

et al. 2011

Circulation Research

244

237

View full text Add to dashboard Cite

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“…88 Finally, mutations in SNTA1 have also been linked to SIDS. 108 Ackerman and colleagues screened 292 SIDS cases, and identified 6 distinct SNTA1 mutations (p.G54R, p.P56S, p.T262P, p.S287R, p.T372M, and p.G460S) in 8 cases. Interestingly, when coexpressed with Na v 1.5 in HEK-293 cells, the p.G54R and p.P56S mutations did not affect I Na compared with wild-type SNTA1.…”

Section: Wilde and Brugadamentioning

confidence: 99%

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

Wilde

Brugada

2011

Circulation Research

190

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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“…Cheng et al (Cheng et al 2009) reported a mutation in α1-syntrophin (SNTA1) as a novel cause of long QT syndrome in sudden death infant syndrome (SIDS), and Tan et al (Tan et al 2010) suggested a mutation in the β subunit of the Na v 1.5 cardiac sodium channel as a cause of arrhythmia in SIDS. Mutations not only in ion channels but also in cardiac gap junction channels may cause conduction defects and lead to sudden death in children (SIDS).…”

Section: Channelopathiesmentioning

confidence: 99%

Role of risk stratification and genetics in sudden cardiac death

Rai

Agrawal

2017

Can. J. Physiol. Pharmacol.

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Keyword:Sudden cardiac death, coronary artery disease, heart failure, Arrhythmias, Atrial fibrillation https://mc06.manuscriptcentral.com/cjpp-pubs AbstractSudden cardiac death (SCD) is a major public health issue due to its increasing incidence in the general population and the difficulty in identifying high-risk individuals.Nearly 300,000-350,000 patients in the United States and 4-to 5 million patients in the world die from SCD. Coronary artery disease and advanced heart failure are the main etiology for SCD. Ischemia of any cause precipitates lethal arrhythmias, and ventricular tachycardia and ventricular fibrillation are the most common lethal arrhythmias precipitating SCD. Pulse-less electrical activity, brady-arrhythmia and electromechanical dissociation also result in SCD.Most sudden cardiac deaths occur out-of-the-hospital setting, so it is difficult to estimate the public burden, which results in overestimating the incidence of SCD. The insufficiency and limited predictive value of various indicators and criteria for SCD result in the increasing incidences. As a result, there is a need to develop better risk stratification criteria and find modifiable variables to decrease the incidence. Primary and secondary prevention and treatment of SCD need further research. This critical review is focused on the etiology, risk factors, prognostic factors and importance of risk stratification of SCD.Key words: Sudden cardiac death, Coronary artery disease, Heart failure, Arrhythmias, Atrial fibrillation, Ventricular fibrillation, Channelopathies, Risk stratification, Prevention

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α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Cited by 85 publications

References 48 publications

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

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

Role of risk stratification and genetics in sudden cardiac death

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α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Cited by 85 publications

References 48 publications

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na v 1.5 in Cardiomyocytes

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na v 1.5 in Cardiomyocytes

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

Role of risk stratification and genetics in sudden cardiac death

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Product

Resources

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SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes