Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy
Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy
复制标题
DOI：
10.1161/circresaha.109.194423
复制
发表时间：
2009-06-05
影响因子：
20.1
通讯作者：
Bezzina, Connie R.
中科院分区：
文献类型：
--
作者：
Remme, Carol Ann;Scicluna, Brendon P.;Bezzina, Connie R.
传导：驱动心跳的电脉冲减慢可能引起致命的心律失常。编码成孔的心脏钠通道α亚基的SCN5A突变与基于传导减慢的家族性心律失常综合征有关。然而，突变携带者的疾病严重程度是高度可变的。我们假设遗传修饰因子是传导减慢和疾病严重程度变化的基础。为了鉴定这些修饰因子，我们研究了2种不同小鼠品系FVB/N和129P2的Scn5a（1798insD/+）突变。在129P2小鼠中，与FVB/N相比，突变导致更严重的传导减慢，特别是在右心室（RV）。两种小鼠品系的泛基因组mRNA表达谱显示，与FVB/N相比，129P2小鼠中编码钠通道辅助亚基β 4 （Scn4b）的mRNA显著减少。这与129P2脑室组织中低至无法检测到的β 4蛋白水平相对应，而FVB/N中检测到丰富的β 4蛋白。对2种小鼠分离肌细胞的钠电流测量表明，与FVB/N相比，129P2小鼠肌细胞的钠通道激活发生在更多的正电位下。通过计算机模拟，这种激活动力学的差异被预测为解释在2个菌株之间观察到的传导疾病严重程度的差异。总之，基因决定的钠电流特征在心肌细胞水平上的差异调节了心脏钠通道病变的疾病严重程度。特别是，钠通道亚基β 4 （SCN4B）可能构成传导和心脏钠通道疾病的潜在遗传修饰因子。（Circ Res. 2009; 104: 1283-1292.）
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.)