Review ArticleCardiac Sodium Channel Overlap Syndromes: Different Faces of SCN5A Mutations
Introduction
The cardiac voltage-gated sodium channel is responsible for the initial fast upstroke of the action potential and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. During common pathological conditions such as myocardial ischemia and heart failure, decreased sodium current function may cause conduction disturbances and potentially life-threatening arrhythmias (Cascio, 2001, Tomaselli and Zipes, 2004). In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of relatively uncommon arrhythmia syndromes, including long-QT syndrome type 3 (LQT3), Brugada syndrome, conduction disease, sinus node dysfunction, and atrial standstill, which potentially lead to fatal arrhythmias in otherwise healthy young individuals (Tan et al. 2003). Originally, these various arrhythmia syndromes were seen as separate clinical entities and mutations causing LQT3 syndrome and Brugada syndrome or conduction disease were considered to cause opposite biophysical effects on sodium current availability. In contrast, recent reports indicate that these disorders show more overlap than previously appreciated in both clinical symptoms and biophysical properties of the mutant sodium channels involved. To gain more insight into this complicated issue, we provide an overview of the molecular, biophysical, genetic, and clinical characteristics of these overlap syndromes of cardiac sodium channelopathy.
Section snippets
Cardiac Sodium Channel Structure, Function, and Regulation
The cardiac sodium channel is a member of the voltage-dependent family of sodium channels, which consist of heteromeric assemblies of the pore-forming α-subunit with an ancillary modulatory β-subunit (see George 2005). The human cardiac sodium channel α-subunit protein (designated Nav1.5) encoded by the SCN5A gene (located on chromosome 3p21) is made up of four internally homologous domains (DI-DIV), each consisting of six transmembrane α-helical segments (S1-S6) (Figure 1). The positively
Mutations in SCN5A: A Clinical and Genetic Perspective
More than a decade ago, the LQT3 locus was mapped to chromosome 3p21-24, and the first SCN5A mutation, comprising a deletion of three conserved amino acids, delKPQ1505-1507, in the cytoplasmic linker between domains DIII and DIV, was subsequently reported in two unrelated LQT3 syndrome families (Wang et al. 1995). In 1998, mutations in SCN5A were also described in patients with Brugada syndrome, a familial disease entity comprising specific ECG abnormalities (ST-segment elevation in the
Overlap Syndrome in Sodium Channel Disease: A Biophysical Perspective
From a biophysical point of view, SCN5A mutations can lead to multiple rhythm disturbances through a variety of defects affecting different properties of the sodium channel (Viswanathan and Balser 2004). In LQT3, mutations classically disrupt fast inactivation of the sodium current, allowing for sodium channels to reopen, resulting in a persistent inward current during the action potential plateau phase, with subsequent delayed repolarization and QT prolongation (gain of function mutations) (
Clinical Factors Influencing Disease Expressivity in Sodium Channel Overlap Syndrome
Although the diverse clinical and biophysical characteristics of SCN5A mutations related to overlap syndromes have been extensively investigated, it still remains unclear why one particular mutation leads to a predominantly LQT3 phenotype in one patient, and to Brugada syndrome, conduction disease, or a mixed clinical phenotype in another mutation carrier. Sex is a well-known modifier of ECG phenotype and arrhythmia manifestations in both LQTS and Brugada syndrome (Priori et al., 2003, Gehi et
Genetic Modifiers in Cardiac Sodium Channel Disease
The reduced disease penetrance and variable disease expression observed in 1795insD carriers as well as other sodium channel overlap syndromes clearly suggest a potential role for genetic modifiers (Van den Berg et al., 2001, Kyndt et al., 2001, Probst et al., 2003). Here, different genetic mechanisms may be involved. In some instances, coinheritance of a second mutation (compound mutations) in SCN5A may account for more severe phenotypic manifestations of conduction disease and Brugada
Overlap Syndrome in Other Sodium Channelopathies
Mutations in voltage-gated sodium channel genes other than SCN5A are associated with neuronal and muscle channelopathies (for review, see Koopmann et al. 2006). Several forms of epilepsy have been described in relation to mutations in the α-subunits SCN1A and SCN2A, as well as the β-subunit SCN1B (see Meisler and Kearney 2005), whereas SCN8A mutations cause cerebellar ataxia and behavioral abnormalities (Trudeau et al. 2006), and mutations in SCN9A have been associated with peripheral nerve
Conclusion
In the past decade, an increasing number of SCN5A mutations have been described in patients with long-QT syndrome type 3, Brugada syndrome, (progressive) conduction disease, atrial standstill, and sick sinus syndrome. Although originally considered separate entities, various SCN5A-related arrhythmia syndromes are now known to display mixed phenotypes, known as cardiac sodium channel overlap syndromes. In many cases, multiple biophysical defects of single SCN5A mutations underlie the overlapping
Acknowledgments
This work was supported by the Netherlands Heart Foundation (Grants 2003B195 and 2003T302), by the Interuniversity Cardiology Institute of the Netherlands (ICIN project 27) and by a Leducq Foundation Transatlantic Network of Excellence award (Alliance Against Sudden Cardiac Death). CR Bezzina is an Established Investigator of the Netherlands Heart Foundation (2005T024).
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