SCN5A Polymorphism Restores Trafficking of a Brugada Syndrome Mutation on a Separate Gene

Abstract

Background-Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation. Methods and Results-In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other. Conclusions-This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels. (Circulation. 2006;114:368-376.)

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

“…H558R, an A to G mutation at position 1673, which causes the substitution of histidine for arginine at position 558, may be associated with sodium‐channel inactivation, but not as strong as R1193Q 24. The results of this study supported this hypothesis, evidenced by the prolongation of PR interval, but not significant QRS widening, in BrS patients with the presence of H558R (Table 4).…”

Identification of Six Novel SCN5A Mutations in Japanese Patients With Brugada Syndrome

“…H558R (identified in patients B22 and B24) is the most common SCN5A polymorphism that mitigates the effects of the loss of function mutation. 20,[23][24][25] Since patient B22 carries both a heterozygous S1553R and a homozygous H558R, there is a possibility that H558R may ameliorate the clinical severity of this patient. P1090L (identified in patients B10, B15, and B25) and R1193Q (identified in patients B02 and B24) are Asian-specific polymorphisms, 20,26,27) although R1193Q has also been reported as a BrS and LQTScausing mutation.…”

H558R polymorphism in SCN5A is associated with Keshan disease and QRS prolongation in Keshan disease patients

“…To the best of our knowledge, this is the first report about the SNP H558R in KSD patients, which could be found both in the KSD group and the region-matched control group (Viswanathan et al, 2003;Ye et al, 2003;Poelzing et al, 2006;Gui et al, 2010). The present study hypothesized that the H558R polymorphism of the SCN5A gene was a predisposing factor for KSD.…”

“…Its functional significance in modulating the concomitant mutated SCN5A-induced change in ion channel property has been shown in previous studies. For example, H558R can upregulate the functions of cardiac sodium channels with loss-of-function mutations, such as R282H (Poelzing et al, 2006) and D1275N (Gui et al, 2010). When the two mutants were coexpressed in human embryonic kidney cells (HEK293) with R558, significantly greater currents were produced than those produced by coexpressing the mutants with H558R.…”