title: Loss-of-function mutation of the SCN3B-encoded sodium channel {beta}3 subunit associated with a case of idiopathic ventricular fibrillation.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  This study provides molecular and cellular evidence implicating mutations in Navbeta3 as a cause of IVF.
authors.affiliation: Department of Medicine, Cardiovascular Section, and the Cardiac Molecular Arrhythmias Research Program, University of Wisconsin-Madison, 600 Highland Avenue H6/349, Madison, WI 53792, USA.
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Valdivia
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Win-Kuang
authors.initials: WK
authors.lastname: Shen
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Algiers
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D047548:Defibrillators; D017147:Defibrillators, Implantable; D004554:Electric Countershock / Q000295:instrumentation; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease; D006801:Humans; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000378:metabolism; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D021381:Protein Transport; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D062549:Voltage-Gated Sodium Channel beta-3 Subunit; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C493324:SCN3B protein, human; C568320:SCN5A protein, human; D015222:Sodium Channels; D062549:Voltage-Gated Sodium Channel beta-3 Subunit