Cardiac potassium channel dysfunction in sudden infant death syndrome
Cardiac potassium channel dysfunction in sudden infant death syndrome
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DOI：
10.1016/j.yjmcc.2007.11.015
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发表时间：
2008-03-01
影响因子：
5
通讯作者：
George, Alfred L., Jr.
中科院分区：
文献类型：
--
作者：
Rhodes, Troy E.;Abraham, Robert L.;George, Alfred L., Jr.
危及生命的心律失常被怀疑是婴儿猝死综合征（SIDS）的原因之一，这一假设得到了心律失常易感基因突变发生在5-10%病例中的观察结果的支持。然而，与SIDS相关的心脏钾通道基因突变的功能后果以及这些等位基因如何可能在机械上易患猝死尚不清楚。为了解决这些问题，我们研究了四个错义KCNH 2（编码HERG）变异，一个复合KCNH 2基因型，和错义KCNQ 1突变所有以前在挪威SIDS病例中发现。六种变体中的三种表现出功能障碍，而三种与野生型通道（KCNH 2变体V279 M、R885 C和S1040 G）在生物药理学上相似。当与WT HERG共表达时，R273 Q和K897 T/R954 C产生的电流类似于心脏延迟整流电流（I-Kr）的快速分量，但幅度显著降低。动作电位建模表明，这种水平的功能障碍足以引起动作电位时程增加和暂停依赖性早期后除极。相比之下，KCNQ 1 - 1274 V导致I-KS的功能增益，其特征在于增加的电流密度、更快的激活和更慢的失活，导致在重复刺激时瞬时电流的积累。采用马尔可夫模型的杂合子1274 V-I-Ks纳入罗-鲁迪（LRd）心室细胞模型的动作电位模拟表明，明显的速率依赖性缩短的动作电位时程预测短QT表型。我们的研究结果表明，与STDS相关的某些钾通道突变赋予明显的功能缺陷，与LQTS或SQTS一致，并进一步强调了先天性心律失常易感性在该综合征中的作用。(C)2007爱思唯尔公司All rights reserved.
Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wildtype channels (KCNH2 variants V279M, R885C, and S 1040G). When co-expressed with WT HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I-Kr) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-1274V causes a gain-of-function in I-KS characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous 1274V-I-Ks incorporated into the Luo-Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with STDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome. (C) 2007 Elsevier Inc. All rights reserved.