Cardiac Sodium Channel Mutations: Why so Many Phenotypes?

M. Liu, K. C. Yang, S. C. Dudley

Research output: Chapter in Book/Report/Conference proceedingChapter

15 Scopus citations


The cardiac Na+ channel (Nav1.5) conducts a depolarizing inward Na+ current that is responsible for the generation of the upstroke Phase 0 of the action potential. In heart tissue, changes in Na+ currents can affect conduction velocity and impulse propagation. The cardiac Nav1.5 is also involved in determination of the action potential duration, since some channels may reopen during the plateau phase, generating a persistent or late inward current. Mutations of cardiac Nav1.5 can induce gain or loss of channel function because of an increased late current or a decrease of peak current, respectively. Gain-of-function mutations cause Long QT syndrome type 3 and possibly atrial fibrillation, while loss-of-function channel mutations are associated with a wider variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, dilated cardiomyopathy, and sick sinus node syndrome. The penetrance and phenotypes resulting from Nav1.5 mutations also vary with age, gender, body temperature, circadian rhythm, and between regions of the heart. This phenotypic variability makes it difficult to correlate genotype–phenotype. We propose that mutations are only one contributor to the phenotype and additional modifications on Nav1.5 lead to the phenotypic variability. Possible modifiers include other genetic variations and alterations in the life cycle of Nav1.5 such as gene transcription, RNA processing, translation, posttranslational modifications, trafficking, complex assembly, and degradation. In this chapter, we summarize potential modifiers of cardiac Nav1.5 that could help explain the clinically observed phenotypic variability. Consideration of these modifiers could help improve genotype–phenotype correlations and lead to new therapeutic strategies.

Original languageEnglish (US)
Title of host publicationNa Channels from Phyla to Function, 2016
EditorsSergei Yu. Noskov, Robert J. French
PublisherAcademic Press Inc.
Number of pages47
ISBN (Print)9780128053867
StatePublished - 2016
Externally publishedYes

Publication series

NameCurrent Topics in Membranes
ISSN (Print)1063-5823

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.


  • Channelopathies
  • Genetic and genomic background
  • Genotype–phenotype variability
  • Ion homeostasis
  • Posttranslational modifiers
  • Transcriptional modifiers
  • Translational modifiers


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