TY - JOUR
T1 - Loss-of-function mutation of the SCN3B-encoded sodium channel 3 subunit associated with a case of idiopathic ventricular fibrillation
AU - Valdivia, Carmen R.
AU - Medeiros-Domingo, Argelia
AU - Ye, Bin
AU - Shen, Win Kuang
AU - Algiers, Timothy J.
AU - Ackerman, Michael J.
AU - Makielski, Jonathan C.
N1 - Funding Information:
This work was supported by the University of Wisconsin Cellular and Molecular Arrhythmia Research Program (J.C.M.) and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (M.J.A.), the Established Investigator Award from the American Heart Association (M.J.A.), and the National Institutes of Health HD42569 (M.J.A.) and HL71092 (J.C.M.).
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Channel subunit
KW - Inherited arrhythmia
KW - Na-channel
KW - Sudden death
KW - Ventricular arrhythmia
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U2 - 10.1093/cvr/cvp417
DO - 10.1093/cvr/cvp417
M3 - Article
C2 - 20042427
AN - SCOPUS:77952394129
SN - 0008-6363
VL - 86
SP - 392
EP - 400
JO - Cardiovascular research
JF - Cardiovascular research
IS - 3
ER -