A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.
BACKGROUND
Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.


RESULTS
A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the beta 3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of Na(V)beta 3 in human ventricular myocardium.


CONCLUSIONS
Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNa(v)1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.
Hu
Dan
D
Masonic Medical Research Laboratory, Utica, NY, USA.
Barajas-Martinez
Hector
H
Burashnikov
Elena
E
Springer
Michael
M
Wu
Yuesheng
Y
Varro
Andras
A
Pfeiffer
Ryan
R
Koopmann
Tamara T
TT
Cordeiro
Jonathan M
JM
Guerchicoff
Alejandra
A
Pollevick
Guido D
GD
Antzelevitch
Charles
C
D000595:Amino Acid Sequence; D053840:Brugada Syndrome / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D002460:Cell Line; D004562:Electrocardiography; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D062549:Voltage-Gated Sodium Channel beta-3 Subunit
D011993:Recombinant Fusion Proteins; C493324:SCN3B protein, human; D015222:Sodium Channels; D062549:Voltage-Gated Sodium Channel beta-3 Subunit; D049452:Green Fluorescent Proteins