PubMed 19407241
Referenced in: none
Automatically associated channels: Nav1.5 , Slo1
Title: Genetically determined differences in sodium current characteristics modulate conduction disease severity in mice with cardiac sodium channelopathy.
Authors: Carol Ann Remme, Brendon P Scicluna, Arie O Verkerk, Ahmad S Amin, Sandra van Brunschot, Leander Beekman, Vera H M Deneer, Catherine Chevalier, Fumitaka Oyama, Haruko Miyazaki, Nobuyuki Nukina, Ronald Wilders, Denis Escande, Rémi Houlgatte, Arthur A M Wilde, Hanno L Tan, Marieke W Veldkamp, Jacques M T de Bakker, Connie R Bezzina
Journal, date & volume: Circ. Res., 2009 Jun 5 , 104, 1283-92
PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19407241
Abstract
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 alpha 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(1798insD/+) 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 beta4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta4 protein levels in 129P2 ventricular tissue, whereas abundant beta4 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 beta4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.