Dumaine R, Towbin J A, Brugada P, Vatta M, Nesterenko D V, Nesterenko V V, Brugada J, Brugada R, Antzelevitch C
Departments of Molecular Biology and Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA.
Circ Res. 1999 Oct 29;85(9):803-9. doi: 10.1161/01.res.85.9.803.
The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.
布加综合征是猝死的主要原因，在东南亚和日本裔年轻男性中尤为常见。该综合征在心电图上的特征是V1至V3导联ST段抬高以及可恶化为心室颤动的快速多形性室性心动过速。我们团队最近将该疾病与SCN5A基因突变联系起来，SCN5A基因编码心脏钠通道的α亚基。当在蛙卵母细胞中异源表达时，从Thr1620Met错义突变体记录的电生理数据未能充分解释心电图表型。因此，我们试图进一步表征该突变体的电生理学特性。我们假设在更接近生理的温度下，错义突变可能会改变钠通道的门控，使得在右心室动作电位的早期阶段净外向电流显著增加。在本研究中，我们通过在哺乳动物细胞系中表达Thr1620Met来验证这一假设，使用膜片钳技术在32℃下研究电流。我们的结果表明，在32℃时，与野生型相比，Thr1620Met电流的衰减动力学更快。在32℃时，Thr1620Met从失活状态恢复的速度较慢，并且稳态激活明显偏移。我们的研究结果解释了布加综合征患者心电图的特征，首次阐明了一种仅在接近生理范围的温度下才显示出致心律失常性的心脏钠通道突变，并表明一些患者在发热状态下可能更易发生危险。
