The SCN5A gene encodes the alpha subunit of the human heart sodium channel 
(hH1), which plays a critical role in cardiac excitability. Mutations of SCN5A 
underlie Brugada syndrome, an inherited disorder that leads to ventricular 
fibrillation and sudden death. This study describes changes in cellular 
localization and functional expression of hH1 in a naturally occurring SCN5A 
mutation (R1432G) reported for Brugada syndrome. Using patch-clamp experiments, 
we show that there is an abolition of functional hH1 expression in R1432G 
mutants expressed in human tsA201 cells but not in Xenopus oocytes. In tsA201 
cells, a conservative positively charged mutant, R1432K, produced sodium 
currents with normal gating properties, whereas other mutations at this site 
abolished functional sodium channel expression. Immunofluorescent staining and 
confocal microscopy showed that the wild-type alpha subunit expressed in tsA201 
cells was localized to the cell surface, whereas the R1432G mutant was 
colocalized with calnexin within the endoplasmic reticulum. The beta(1) subunit 
was also localized to the cell surface in the presence of the alpha subunit; 
however, in its absence, the beta(1) subunit was restricted to a perinuclear 
localization. These results demonstrate that the disruption of SCN5A 
cell-surface localization is one mechanism that can account for the loss of 
functional sodium channels in Brugada syndrome. The full text of this article is 
available at http://www.circresaha.org.