SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene.
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.


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.
Poelzing
Steven
S
Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Rammelkamp 658, Cleveland, OH 44109-1998, USA.
Forleo
Cinzia
C
Samodell
Melissa
M
Dudash
Lynn
L
Sorrentino
Sandro
S
Anaclerio
Matteo
M
Troccoli
Rossella
R
Iacoviello
Massimo
M
Romito
Roberta
R
Guida
Pietro
P
Chahine
Mohamed
M
Pitzalis
Mariavittoria
M
Deschênes
Isabelle
I
D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D004247:DNA / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004594:Electrophysiology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics* / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D012307:Risk Factors; D015222:Sodium Channels / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D013577:Syndrome
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011506:Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D004247:DNA