BACKGROUND: We identified 2 compound heterozygous mutations (p.D1690N and 
p.G1748D) in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) in a 
proband diagnosed with Brugada syndrome type 1. Furthermore, in the allele 
encoding the p.D1690N mutation, the p.H558R polymorphism was also detected.
OBJECTIVE: The purpose of this study was to analyze the functional properties of 
the mutated channels as well as the putative modulator effects produced by the 
presence of the polymorphism.
METHODS: Wild-type and mutated human Nav1.5 channels were expressed in Chinese 
hamster ovary cells and recorded using whole-cell patch-clamp technique.
RESULTS: Separately, both p.D1690N and p.G1748D mutations produced a marked 
reduction in peak Na(+) current density (>80%), mainly due to their limited 
trafficking toward the membrane. Furthermore, p.G1748D mutation profoundly 
affected channel gating. Both p.D1690N and p.G1748D produced a marked dominant 
negative effect when cotransfected with either wild-type or p.H558R channels. 
Conversely, p.H558R was able to rescue defective trafficking of p.D1690N 
channels toward the membrane when both polymorphism and mutation were in the 
same construct. Surprisingly, cotransfection with p.D1690N, either alone or 
together with the polymorphism (p.H558R-D1690N), completely restored the 
profound gating defects exhibited by p.G1748D channels but only slightly rescued 
their trafficking.
CONCLUSIONS: Our results add further support to the hypothesis that Nav1.5 
subunits interact among them before trafficking toward the membrane and suggest 
that a missense mutation can "rescue" the defective gating produced by another 
missense mutation.