title: 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.
  
  
  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.
authors.affiliation: Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Rammelkamp 658, Cleveland, OH 44109-1998, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
authors.forename: Cinzia
authors.initials: C
authors.lastname: Forleo
authors.forename: Melissa
authors.initials: M
authors.lastname: Samodell
authors.forename: Lynn
authors.initials: L
authors.lastname: Dudash
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorrentino
authors.forename: Matteo
authors.initials: M
authors.lastname: Anaclerio
authors.forename: Rossella
authors.initials: R
authors.lastname: Troccoli
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacoviello
authors.forename: Roberta
authors.initials: R
authors.lastname: Romito
authors.forename: Pietro
authors.initials: P
authors.lastname: Guida
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
authors.forename: Mariavittoria
authors.initials: M
authors.lastname: Pitzalis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschênes
mesh_terms: 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
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011506:Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D004247:DNA