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

Valdivia, Carmen R.; Medeiros Domingo, Argelia; Ye, Bin; Shen, Win-Kuang; Algiers, Timothy J.; Ackerman, Michael J.; Makielski, Jonathan C. (2010). Loss-of-function mutation of the SCN3B-encoded sodium channel {beta}3 subunit associated with a case of idiopathic ventricular fibrillation. Cardiovascular research, 86(3), pp. 392-400. Oxford University Press 10.1093/cvr/cvp417

Full text not available from this repository. (Request a copy)


Loss-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 beta subunits. Here, we report a case with IVF and a novel mutation in the SCN3B-encoded sodium channel beta subunit Navbeta3 that causes a loss of function of Nav1.5 channels in vitro.


Comprehensive open reading frame mutational analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, GPD1L, four sodium channel beta subunit genes (SCN1-4B), and targeted scan of RYR2 was performed. A novel missense mutation, Navbeta3-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 Navbeta3 extracellular domain, and absent in 800 reference alleles. We found that HEK-293 cells had endogenous Navbeta3, but COS cells did not. Co-expression of Nav1.5 with Navbeta3-V54G (with or without co-expression of the Navbeta1 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 Navbeta3 with Nav1.5, and immunocytochemistry demonstrated a dramatic decrease in trafficking to the plasma membrane when co-expressed with mutant Navbeta3-V54G.


This study provides molecular and cellular evidence implicating mutations in Navbeta3 as a cause of IVF.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Medeiros Domingo, Argelia


600 Technology > 610 Medicine & health




Oxford University Press




Argelia Medeiros Domingo

Date Deposited:

19 Jun 2014 13:16

Last Modified:

19 Jun 2014 13:16

Publisher DOI:


PubMed ID:




Actions (login required)

Edit item Edit item
Provide Feedback