SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene.
Circulation
; 114(5): 368-76, 2006 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-16864729
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 ANDRESULTS:
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Arritmias Cardíacas
/
Canais de Sódio
/
Mutação de Sentido Incorreto
/
Polimorfismo de Nucleotídeo Único
/
Proteínas Musculares
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Circulation
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos