Loss-of-function mutation of the SCN3B-encoded sodium channel 3 subunit associated with a case of idiopathic ventricular fibrillation

Carmen R. Valdivia, Argelia Medeiros-Domingo, Bin Ye, Win Kuang Shen, Timothy J. Algiers, Michael J. Ackerman, Jonathan C. Makielski

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

AimsLoss-of-function mutations in the SCN5A-encoded sodium channel SCN5A or Nav1.5 have been identified in idiopathic ventricular fibrillation (IVF) in the absence of Brugada syndrome phenotype. Nav1.5 is regulated by four sodium channel auxiliary β subunits. Here, we report a case with IVF and a novel mutation in the SCN3B-encoded sodium channel β subunit Navβ3 that causes a loss of function of Nav1.5 channels in vitro.Methods and resultsComprehensive open reading frame mutational analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, GPD1L, four sodium channel subunit genes (SCN1-4B), and targeted scan of RYR2 was performed. A novel missense mutation, Navβ3-V54G, was identified in a 20-year-old male following witnessed collapse and defibrillation from VF. The ECG exhibited epsilon waves, and imaging studies demonstrated a structurally normal heart. The mutated residue was highly conserved across species, localized to the Navβ3 extracellular domain, and absent in 800 reference alleles. We found that HEK-293 cells had endogenous Navβ3, but COS cells did not. Co-expression of Nav1.5 with Navβ3-V54G (with or without co-expression of the Nav1 subunit) in both HEK-293 cells and COS cells revealed a significant decrease in peak sodium current and a positive shift of inactivation compared with WT. Co-immunoprecipitation experiments showed association of Navβ3 with Nav1.5, and immunocytochemistry demonstrated a dramatic decrease in trafficking to the plasma membrane when co-expressed with mutant Navβ3-V54G. Conclusion This study provides molecular and cellular evidence implicating mutations in Navβ3 as a cause of IVF.

Original languageEnglish (US)
Pages (from-to)392-400
Number of pages9
JournalCardiovascular research
Volume86
Issue number3
DOIs
StatePublished - Jun 2010

Keywords

  • Channel subunit
  • Inherited arrhythmia
  • Na-channel
  • Sudden death
  • Ventricular arrhythmia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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