Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy

Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel α subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity amo...

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Bibliographic Details
Published in:Circulation research 2009-06, Vol.104 (11), p.1283-1292
Main Authors: Remme, Carol Ann, Scicluna, Brendon P, Verkerk, Arie O, Amin, Ahmad S, van Brunschot, Sandra, Beekman, Leander, Deneer, Vera H.M, Chevalier, Catherine, Oyama, Fumitaka, Miyazaki, Haruko, Nukina, Nobuyuki, Wilders, Ronald, Escande, Denis, Houlgatte, Rémi, Wilde, Arthur A.M, Tan, Hanno L, Veldkamp, Marieke W, de Bakker, Jacques M.T, Bezzina, Connie R
Format: Article
Language:English
Subjects:
Animals
Arrhythmias, Cardiac - physiopathology
Biological and medical sciences
Channelopathies - genetics
Channelopathies - physiopathology
DNA Transposable Elements
Fundamental and applied biological sciences. Psychology
Heart Conduction System - physiopathology
Heart Ventricles - cytology
Heart Ventricles - metabolism
Mice
Mice, Inbred Strains
Muscle Cells - cytology
Muscle Cells - physiology
Mutation
NAV1.5 Voltage-Gated Sodium Channel
RNA, Messenger - genetics
Sodium Channels - deficiency
Sodium Channels - genetics
Sodium Channels - physiology
Vertebrates: cardiovascular system
Voltage-Gated Sodium Channel beta-4 Subunit
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Summary:Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel α subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity among mutation carriers is highly variable. We hypothesized that genetic modifiers underlie the variability in conduction slowing and disease severity. With the aim of identifying such modifiers, we studied the Scn5a mutation in 2 distinct mouse strains, FVB/N and 129P2. In 129P2 mice, the mutation resulted in more severe conduction slowing particularly in the right ventricle (RV) compared to FVB/N. Pan-genomic mRNA expression profiling in the 2 mouse strains uncovered a drastic reduction in mRNA encoding the sodium channel auxiliary subunit β4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable β4 protein levels in 129P2 ventricular tissue, whereas abundant β4 protein was detected in FVB/N. Sodium current measurements in isolated myocytes from the 2 mouse strains indicated that sodium channel activation in myocytes from 129P2 mice occurred at more positive potentials compared to FVB/N. Using computer simulations, this difference in activation kinetics was predicted to explain the observed differences in conduction disease severity between the 2 strains. In conclusion, genetically determined differences in sodium current characteristics on the myocyte level modulate disease severity in cardiac sodium channelopathies. In particular, the sodium channel subunit β4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.109.194423