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

Abstract

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...

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies

“…Such repolarization abnormalities have also been seen in long QT syndrome type 3 (LQTS3) as a result of gain-of-function SCN5A mutations. 40 We were, however, unable to demonstrate prolonged QTc intervals in association with p. . In LQTS3, prolongation of the QT interval is expected to result from decreased K + repolarization currents, increased Ca 2+ entry or a sustained entry of Na + (late I Na ) into the cardiomyocyte.…”

“…In LQTS3, prolongation of the QT interval is expected to result from decreased K + repolarization currents, increased Ca 2+ entry or a sustained entry of Na + (late I Na ) into the cardiomyocyte. 40 Whether a parallelism can be drawn for SCN4A and if SCN4A mutations might result in overlapping clinical properties of different syndromes such as BS and LQTS3 41 requires further investigation.…”

Turbulent electrical activity at sharp-edged inexcitable obstacles in a model for human cardiac tissue

“…Similar questions arise in various forms of genetic diseases, such as in the Brugada syndrome, in which there is a 50% I Na loss of function localized in the right ventricular outflow tract; this is considered severe (8,79). However, in addition to the change in I Na , the Brugada syndrome is also associated with several other changes, e.g., an increase in the fibrosis of cardiac tissue (15).…”

Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel

“…Inherited mutations in Na V β-subunit genes can result in a variety of human disorders, including severe epilepsy (47)(48)(49)(50), cardiac arrhythmia (51,52), and are associated with cancer (53) and neuropsychiatric disorders (54,55). The underlying stoichiometry, putative interacting surfaces and mechanisms of β-subunit modulation of Na V s remains poorly understood.…”