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

Circulation. 2006 Aug 1;114(5):368-76. doi: 10.1161/CIRCULATIONAHA.105.601294. Epub 2006 Jul 24.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology*
  • Cell Line
  • Cell Membrane / chemistry
  • Cell Membrane / physiology
  • DNA / genetics
  • Death, Sudden, Cardiac / etiology
  • Electrophysiology
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunohistochemistry
  • Male
  • Muscle Proteins / analysis
  • Muscle Proteins / genetics*
  • Muscle Proteins / physiology*
  • Mutation, Missense / genetics*
  • Mutation, Missense / physiology
  • NAV1.5 Voltage-Gated Sodium Channel
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics*
  • Polymorphism, Single Nucleotide / physiology
  • Proteins / metabolism
  • Risk Factors
  • Sodium Channels / analysis
  • Sodium Channels / genetics*
  • Sodium Channels / physiology*
  • Syndrome


  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • Proteins
  • SCN5A protein, human
  • Sodium Channels
  • DNA