Abstract
Since the identification of the first SCN5A mutation associated with long QT syndrome in 1995, several mutations in this gene for the α subunit of the cardiac sodium channel have been identified in a heterogeneous subset of cardiac rhythm syndromes, including Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation and dilated cardiomyopathy. Robust clinical evidence has been accompanied by bench studies performed in different models spanning from in vitro expression systems to transgenic mice. Together, these studies have helped establish genotype–phenotype correlations and have shaped our understanding of the role of the cardiac sodium channel in health and in disease. Remarkably, these advances in understanding have impacted on clinical management by allowing us to start developing gene-specific risk stratification schemes and mutation-specific management strategies. In this Review, we summarize the current understanding of the molecular mechanism of SCN5A-associated inherited arrhythmias, focusing on the most recent development of mutation-specific management in SCN5A-associated long QT syndrome type 3. We also briefly discuss arrhythmia-causing mutations in the genes encoding the β subunit of the cardiac sodium channel and in those encoding proteins in the associated macromolecular complex.
Key Points
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The α subunit of the cardiac sodium channel is encoded by the SCN5A gene; most mutations that affect the sodium current in the heart are found in this gene
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Mutations in the SCN5A gene are associated with long QT syndrome, Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation, dilated cardiomyopathy and overlapping syndromes
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Mutations in genes encoding the β subunit of the cardiac sodium channel and in those encoding proteins in the associated macromolecular complex can also cause arrhythmias
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The biophysical characterization of SCN5A mutations allows us to explain, at least in part, the clinical phenotypes observed in patients
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A gene-specific approach is required for risk stratification and treatment of patients with long QT syndrome type 3
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In vitro studies of SCN5A mutations have identified sets of biophysical properties that might be used to predict patients' responses to therapy
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Ruan, Y., Liu, N. & Priori, S. Sodium channel mutations and arrhythmias. Nat Rev Cardiol 6, 337–348 (2009). https://doi.org/10.1038/nrcardio.2009.44
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DOI: https://doi.org/10.1038/nrcardio.2009.44
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