Department of Medical Biology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Int J Mol Sci. 2018 Feb 23;19(2):634. doi: 10.3390/ijms19020634.
The gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (). The 1795insD mutation in causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 beats/min in non-carriers from the same family (lowest heart rate 41 vs. 47 beats/min). To unravel the underlying mechanism, we incorporated the mutation-induced changes in into a recently developed comprehensive computational model of a single human sinoatrial node cell (Fabbri-Severi model). The 1795insD mutation reduced the beating rate of the model cell from 74 to 69 beats/min (from 49 to 43 beats/min in the simulated presence of 20 nmol/L acetylcholine). The mutation-induced persistent per se resulted in a substantial increase in beating rate. This gain-of-function effect was almost completely counteracted by the loss-of-function effect of the reduction in conductance. The further loss-of-function effect of the shifts in steady-state activation and inactivation resulted in an overall loss-of-function effect of the 1795insD mutation. We conclude that the experimentally identified mutation-induced changes in can explain the clinically observed sinus bradycardia. Furthermore, we conclude that the Fabbri-Severi model may prove a useful tool in understanding cardiac pacemaker activity in humans.
该基因编码离子通道的孔形成α亚基，该通道携带心脏快速钠电流（）。中的 1795insD 突变导致窦性心动过缓，突变携带者的平均心率为 70 次/分钟，而来自同一家庭的非携带者的平均心率为 77 次/分钟（最低心率为 41 次/分钟与 47 次/分钟）。为了揭示潜在的机制，我们将突变诱导的变化纳入了最近开发的单个人心房结细胞（法布里-塞维里模型）的综合计算模型中。1795insD 突变使模型细胞的搏动率从 74 次/分钟降至 69 次/分钟（在模拟存在 20 毫摩尔/升乙酰胆碱的情况下，从 49 次/分钟降至 43 次/分钟）。突变诱导的持续存在本身导致搏动率显著增加。这种功能获得效应几乎完全被 电导降低的功能丧失效应抵消。稳态激活和失活的变化进一步导致功能丧失效应，导致 1795insD 突变的整体功能丧失效应。我们得出结论，实验中确定的突变诱导的变化可以解释临床上观察到的窦性心动过缓。此外，我们得出结论，法布里-塞维里模型可能被证明是理解人类心脏起搏器活动的有用工具。
