TY - JOUR
T1 - Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy
AU - Remme, Carol Ann
AU - Scicluna, Brendon P.
AU - Verkerk, Arie O.
AU - Amin, Ahmad S.
AU - van Brunschot, Sandra
AU - Beekman, Leander
AU - Deneer, Vera H. M.
AU - Chevalier, Catherine
AU - Oyama, Fumitaka
AU - Miyazaki, Haruko
AU - Nukina, Nobuyuki
AU - Wilders, Ronald
AU - Escande, Denis
AU - Houlgatte, Remi
AU - Wilde, Arthur A. M.
AU - Tan, Hanno L.
AU - Veldkamp, Marieke W.
AU - de Bakker, Jacques M. T.
AU - Bezzina, Connie R.
PY - 2009
Y1 - 2009
N2 - 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 beta 4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta 4 protein levels in 129P2 ventricular tissue, whereas abundant beta 4 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 beta 4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease. (Circ Res. 2009; 104: 1283-1292.)
AB - 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 beta 4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta 4 protein levels in 129P2 ventricular tissue, whereas abundant beta 4 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 beta 4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease. (Circ Res. 2009; 104: 1283-1292.)
U2 - https://doi.org/10.1161/CIRCRESAHA.109.194423
DO - https://doi.org/10.1161/CIRCRESAHA.109.194423
M3 - Article
C2 - 19407241
SN - 0009-7330
VL - 104
SP - 1283-U112
JO - Circulation Research
JF - Circulation Research
IS - 11
ER -