SCN5A channelopathies – An update on mutations and mechanisms

Abstract

Voltage-gated Na⁺ channels mediate the rapid upstroke of the action potential in excitable tissues. Na_v1.5, encoded by the SCN5A gene, is the predominant isoform in the heart. Mutations in SCN5A are associated with distinct cardiac excitation disorders often resulting in life-threatening arrhythmias. This review outlines the currently known SCN5A mutations linked to three distinct cardiac rhythm disorders: long QT syndrome subtype 3 (LQT3), Brugada syndrome (BS), and cardiac conduction disease (CCD). Electrophysiological properties of the mutant channels are summarized and discussed in terms of Na⁺ channel structure–function relationships and regarding molecular mechanisms underlying the respective cardiac dysfunction. Possible reasons for less convincing genotype–phenotype correlations are suggested.