A Mutation in the β3 Subunit of the Cardiac Sodium Channel Associated With Brugada ECG Phenotype
| Autor: | Yuesheng Wu, Elena Burashnikov, Tamara T. Koopmann, Jonathan M. Cordeiro, Charles Antzelevitch, Ryan Pfeiffer, Guido D. Pollevick, Alejandra Guerchicoff, András Varró, Michael Springer, Hector Barajas-Martinez, Dan Hu |
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| Přispěvatelé: | Cardiology |
| Rok vydání: | 2009 |
| Předmět: |
Male
Patch-Clamp Techniques Recombinant Fusion Proteins Green Fluorescent Proteins Mutant Mutation Missense Biology medicine.disease_cause Article Sodium Channels Cell Line Electrocardiography Exon SCN3B SCN1B Genetics medicine Humans Missense mutation Amino Acid Sequence cardiovascular diseases Genetics (clinical) Brugada Syndrome Brugada syndrome Voltage-Gated Sodium Channel beta-3 Subunit Mutation Sodium channel Middle Aged medicine.disease Molecular biology Radiography Phenotype Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation. Cardiovascular genetics, 2(3), 270-278. Lippincott Williams and Wilkins |
| ISSN: | 1942-3268 1942-325X |
| DOI: | 10.1161/circgenetics.108.829192 |
| Popis: | Background— Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene. Methods and Results— A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B , the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A /WT+ SCN1B /WT+ SCN3B /L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a −9.6-mV shift of half-inactivation voltage compared with SCN5A /WT+ SCN1B /WT+ SCN3B /WT. Confocal microscopy revealed that SCN5A /WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B /WT and SCN3B /L10P. Western blot analysis confirmed the presence of Na V β3 in human ventricular myocardium. Conclusions— Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNa v 1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype. |
| Databáze: | OpenAIRE |
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