Dual Variation in SCN5A and CACNB2b Underlies the Development of Cardiac Conduction Disease without Brugada Syndrome

Background: Inherited loss of function mutations in SCN5A have been linked to overlapping syndromes including cardiac conduction disease and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood. Methods: Direct sequencing was performed...

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Published in:Pacing and clinical electrophysiology 2010-03, Vol.33 (3), p.274-285
Main Authors: HU, DAN, BARAJAS-MARTINEZ, HECTOR, NESTERENKO, VLADISLAV V., PFEIFFER, RYAN, GUERCHICOFF, ALEJANDRA, CORDEIRO, JONATHAN M., CURTIS, ANNE B., POLLEVICK, GUIDO D., WU, YUESHENG, BURASHNIKOV, ELENA, ANTZELEVITCH, CHARLES
Format: Article
Language:English
Subjects:
Adolescent
Alleles
Analysis of Variance
Biological and medical sciences
Bradycardia - genetics
Bradycardia - physiopathology
Brugada Syndrome - genetics
Brugada Syndrome - physiopathology
calcium channel
Calcium Channels, L-Type - genetics
Cardiac dysrhythmias
Cardiology. Vascular system
conduction disease
Electrophysiologic Techniques, Cardiac
Female
Heart
Heart Block - genetics
Heart Block - physiopathology
Heart Conduction System - physiopathology
Humans
Male
Medical sciences
Microscopy, Confocal
Middle Aged
Muscle Proteins - genetics
Mutation
NAV1.5 Voltage-Gated Sodium Channel
Pedigree
Phenotype
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
protein trafficking
sodium channel
Sodium Channels - genetics
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Summary:Background: Inherited loss of function mutations in SCN5A have been linked to overlapping syndromes including cardiac conduction disease and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood. Methods: Direct sequencing was performed in a family with cardiac conduction disease. Wild‐type (WT) and mutant channels were expressed in TSA201 cells for electrophysiological study. Green fluorescent protein (GFP)‐fused WT or mutant genes were used to assess channel trafficking. Results: A novel SCN5A mutation, P1008S, was identified in all family members displaying first‐degree atrioventricular block, but not in unaffected family members nor in 430 reference alleles. Peak P1008S current was 11.77% of WT (P < 0.001). Confocal microscopy showed that WT channels tagged with GFP were localized on the cell surface, whereas GFP‐tagged P1008S channels remained trapped in intracellular organelles. Trafficking could be rescued by incubation at room temperature, but not by incubation with mexiletine (300 μM) at 37°C. We also identified a novel polymorphism (D601E) in CACNB2b that slowed inactivation of L‐type calcium current (ICa,L), significantly increased total charge. Using the Luo‐Rudy action potential (AP) model, we show that the reduction in sodium current (INa) can cause loss of the right ventricular epicardial AP dome in the absence but not in the presence of the slowed inactivation of ICa,L. Slowed conduction was present in both cases. Conclusions: Our results suggest genetic variations leading to a loss‐of‐function in INa coupled with a gain of function in ICa,L may underlie the development of cardiac conduction disease without BrS. (PACE 2010; 33:274–285)
ISSN:0147-8389
1540-8159
DOI:10.1111/j.1540-8159.2009.02642.x