Ion channelopathies: a tapped-out mine?
Ion channelopathies: a tapped-out mine?
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离子通道病：一个废弃的矿井？
DOI：
10.1152/ajpheart.01281.2010
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
DudleyJr,SamuelC
中科院分区：
文献类型：
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作者：
DudleyJr,SamuelC
当基廷和同事们在犹他州的山上发现银时，离子通道的研究改变了范式。在分子生物学时代的早期，他们能够描述长QT综合征（一种与特定心电图发现相关的遗传性猝死形式）与离子通道DNA突变之间的遗传联系。他们接着描述了这些突变导致疾病的合理机制。从那时起，这条母矿脉以类似的方式被开采，以描述这些遗传性心脏病的起源，如Brugada综合征、短QT综合征和儿茶酚胺能性多形性室性心动过速（CPVT）（5）。在受影响的个体中识别突变，然后异源表达突变以研究对改变的离子通道的影响，从而开发出合理的机制的挖掘过程已经进行了多次。在发现和研究基因缺陷的过程中，我们了解到的一些主题是，通常在几个不同的离子通道或相关蛋白质中存在许多突变，这些突变可能导致相同的综合征;同一离子通道中的突变可能导致不止一种临床综合征;突变的影响受到遗传背景的调节。“发现并表达”的过程已经变得如此常规，以至于一些人开始质疑是否应该出版基于它的手稿，或者仅仅将结果编入目录（例如，心脏的基因连接，http：//www.密克罗尼西亚联邦。it/cardmoc/）。为了解决这个问题，也许有理由问采矿过程的目的是什么。一些可能的目的包括：1）确定疾病的新机制，2）为受影响的个体开发遗传筛查，3）开发新的治疗方法，以及4）了解更常见的获得性疾病的机制。这一过程因其识别疾病机制的能力而引人注目。例如，长QT综合征是由于复极储备丧失，使得细胞停留在去极化状态太久，允许引起心律失常的膜电位振荡（1）。Brugada综合征似乎与电压门控钠电流丧失有关，导致心脏某些区域的动作电位持续时间突然缩短，以及具有短动作电位的复极化肌细胞和具有长动作电位的去极化肌细胞之间的电流（10）。人们认为电流会引发心律失常。在某些情况下，如CPVT，钙处理的缺陷已被确定，但这种缺陷导致心律失常的实际机制仍然存在争议（2）。挖掘过程也有助于了解更常见的获得性心律失常。例如，人类ether-a-go-go相关基因钾通道的突变被确定为长QT综合征的原因之一，不久之后，该通道与大多数药物诱导的长QT综合征病例有关（7）。尽管取得了成功，但在开发基因筛查工具和开发新疗法方面，该过程的成效却不太高。虽然遗传筛查已经商业化（例如，Familytesting，PGxPredict，New Haven，CT），但不完全的筛查和缺乏一致的基因型-表型相关性使得将信息用于临床决策具有挑战性。治疗方面缺乏发展更令人失望。有一些铅，如钠通道阻滞药长QT 3型（8），NAD+ Brugada.
THE STUDY OF ION CHANNELS shifted paradigms when Keating and colleagues (3) struck silver in the Utah hills. In the early days of the molecular biological era, they were able to describe a genetic linkage between the long QT syndrome, a form of inherited sudden death associated with a particular electrocardiographic finding, and ion channel DNA mutations. They went on to describe a plausible mechanism whereby these mutations caused the disease. Since then, this mother lode has been mined in a similar manner to describe the origins of such inherited arrhythmic conditions such as Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT)(5). The mining process of identifying a mutation in affected individuals and then heterologously expressing the mutation to study the effect on the altered ion channel to develop a plausible mechanism has been played out many times. Some of the themes that have been learned in the course of finding and studying gene defects are that there are many mutations, often in several different ion channels or related proteins, that can cause the same syndrome; that mutations in the same ion channel can give more than one clinical syndrome; and that the effects of mutations are modulated by the genetic context. The “find and express” process has become so routine that some have begun to question whether manuscripts based on it should be published or the results just catalogued (eg, The Gene Connection for the Heart, http://www. fsm. it/cardmoc/). To address that question, it might be reasonable to ask what is the purpose of the mining process. Some possible purposes include the following: 1) identifying new mechanisms of disease, 2) developing genetic screens for affected individuals, 3) developing new therapies, and 4) understanding mechanisms of the more common acquired arrhythmic conditions. The process has been remarkable for its ability to identify the mechanisms of disease. For example, long QT syndrome results from a loss of repolarization reserve such that the cell stays in the depolarized state too long, allowing for membrane potential oscillations that cause the arrhythmia (1). Brugada syndrome seems to be related to a loss of voltage-gated sodium current, causing an abrupt shortening of the action potential duration in certain areas of the heart and current between repolarized myocytes with short action potentials and depolarized myocytes with longer action potentials (10). The current is thought to initiate the arrhythmia. In some cases such as CPVT, a defect in calcium handling has been identified, but the actual mechanism whereby this defect causes the arrhythmia is still debatable (2). The mining process has also been helpful in understanding more commonly occurring acquired arrhythmias. For example, mutations in the human ether-a-go-go-related gene potassium channel were identified as one of the causes of long QT syndrome, and it was not long before this channel was implicated in most of the cases of drug-induced long QT syndrome (7).For all of its successes, the process has been less productive when it comes to developing genetic screening tools and developing new therapies. While genetic screening has been commercialized (eg, Familion Testing, PGxPredict, New Haven, CT), incomplete penetrance and the lack of consistent genotype-phenotype correlations have made using the information for clinical decision making challenging. The lack of development on the treatment side has been even more disappointing. There are some leads, such as sodium channel blocking drugs for long QT type 3 (8), NAD+ for Brugada …