Genetic variants and disease: correlate or cause?
Genetic variants and disease: correlate or cause?
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遗传变异和疾病：相关还是原因？
DOI：
10.1093/eurheartj/ehv516
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发表时间：
2016
影响因子：
39.3
通讯作者：
Pitt,GeoffreyS
中科院分区：
文献类型：
--
作者：
Matsui,Maiko;Pitt,GeoffreyS
随着每一次有节奏的心跳，心房将血液从上到下泵入房室瓣。心室紧随其后，但自下而上收缩，通过各自的流出道喷出血液。心脏传导系统起着大鼓的作用，它首先引导心房泵入等待的心室，然后指示心室从心尖开始收缩。当心肌去极化从窦房结通过房室结和心室传播时，这种从上到下（心房）到下到上（心室）收缩的逆转是通过经由浦肯野纤维的工作心肌的初始电旁路来实现的。连接蛋白40（Cx40）的表达是浦肯野纤维与工作心肌区分的特征之一。这些间隙连接蛋白形成促进电脉冲传播的细胞间孔，并且与主要表达连接蛋白43（Cx43）1的工作心肌相比，Cx40对浦肯野纤维的快速传导特性至关重要（图1A）。证明这种差异表达的是转录因子基因Iroquois homeobox基因3（IRX 3），其是在诱变研究中首次发现的六个Iroquois homeobox转录因子基因（IRX 1-IRX 6）之一，所述诱变研究试图鉴定对果蝇外部感觉器官的模式化重要的基因。2小鼠研究表明，所有六种Irx因子在发育期间和成年期的心脏中都有表达，并且具有不同或重叠的作用。3-5敲除小鼠研究6证明Irx 3在浦肯野纤维中的关键作用，其间接促进Cx40的表达并直接抑制Cx43的表达。Irx 3的消融降低了Cx40，并导致心室传导系统近端分支内Cx43的异位上调。通过改变间隙连接基因的策略表达，浦肯野纤维内激活的有序和系统性传播受到干扰。Cx43的异位表达被认为是特别有问题的，因为它提供了从浦肯野纤维到工作心肌的电连接，从而耗散了流经浦肯野纤维的电活动，导致传导阻滞，但没有缓慢或快速性心律失常。在这种情况下，Koizumi等人在本期报告中指出，IRX 3的功能缺失突变可能是先前未基因分型的心律失常的基础。7他们研究的动机来自于他们对一个独立的Irx 3基因敲除小鼠模型的分析，在该模型中他们观察到了心室异位和非持续性室性心动过速。在Koizumi等人研究的模型中存在室性快速性心律失常以及在先前报道的Irx 3敲除6中不存在室性快速性心律失常的原因尚不清楚，但众所周知，小鼠品系之间的品系差异会强烈影响表型。尽管如此，Koizumi等人继续在130名患有特发性心室颤动、Brugada综合征、早期复极综合征或短QT综合征的患者中寻找IRX 3突变，其中未检测到心脏钠通道基因SCN 5A的突变。在两名患有特发性室颤的患者中，作者发现了不同的IRX 3变体，分别为p.Arg421Pro和p.Pro485Thr。在250名健康志愿者中没有发现任何变异。对于p.Arg421Pro变异，他们还发现了携带者与先证者亲属中异常ECG之间的相关性。对于p.Pro485Thr变异，先证者的母亲和外祖母是携带者，外祖母经历了不明原因的晕厥。作者们...
With each rhythmic heartbeat, the atria pump blood top-to-bottom through the atrioventricular valves. The ventricles follow closely, but contract bottom-to-top to eject blood through their respective outflow tracts. Acting as the drum major is the cardiac conduction system, which first directs the atria to pump into waiting ventricles and then instructs the ventricles to initiate contraction from the apex. As myocardial depolarization spreads from the sinoatrial node through the atrioventricular node and the ventricles, this reversal from top-to-bottom (atria) to bottom-to-top (ventricles) contraction is achieved by an initial electrical bypass of the working myocardium via the Purkinje fibres. Among the features distinguishing Purkinje fibres from the working myocardium is expression of connexin 40 (Cx40). These gap junction proteins form intercellular pores that facilitate electrical impulse propagation, and Cx40 is critical to the rapid conduction properties of the Purkinje fibres compared with the working myocardium, which predominantly expresses connexin 43 (Cx43) 1 (Figure 1 A). Orchestrating this differential expression is the transcription factor gene Iroquois homeobox gene 3 (IRX3), one of six Iroquois homeobox transcription factor genes (IRX1–IRX6) that were first discovered in a mutagenesis study seeking to identify genes important for patterning of external sensory organs of Drosophila. 2 Mouse studies show that all six Irx factors are expressed and have distinct or overlapping roles in the heart during development and in adulthood. 3–5 A knockout mouse study 6 demonstrated critical roles in the Purkinje fibres for Irx3, which indirectly promotes expression of Cx40 and directly represses expression of Cx43. Ablation of Irx3 decreased Cx40 and led to ectopic up-regulation of Cx43 within the proximal branches of the ventricular conduction system. By altering the strategic expression of gap junction genes, the orderly and systematic spread of activation within Purkinje fibres was disturbed. The ectopic expression of Cx43 was postulated to be especially problematic as it provided electrical connections from Purkinje fibres to working myocardium, thereby dissipating electrical activity flowing through the Purkinje fibres, leading to conduction block, but no brady-or tachyarrhythmias. In this context, Koizumi et al. in this issue report that loss-of-function mutations in IRX3 might underlie previously ungenotyped cardiac arrhythmias. 7 Motivation for their study derived from their analysis of an independent Irx3 mouse knockout model in which they observed ventricular ectopy and non-sustained ventricular tachycardia. The reasons for the presence of ventricular tachyarrhythmias in the model studied by Koizumi et al. and their absence in the previously reported Irx3 knockout 6 is not clear, but it is well known that strain differences among mouse lines can strongly influence phenotypes. Nonetheless, Koizumi et al. proceeded to search for IRX3 mutations among 130 patients with idiopathic ventricular fibrillation, Brugada syndrome, early repolarization syndrome, or short-QT syndrome, in whom mutations in the cardiac sodium channel gene SCN5A had not been detected. In two patients who experienced idiopathic ventricular fibrillation, the authors discovered different IRX3 variants, p. Arg421Pro and p. Pro485Thr, respectively. Neither variant was found in 250 healthy volunteers. For the p. Arg421Pro variant, they also found a correlation between carriers and an abnormal ECG among relatives of the proband. For the p. Pro485Thr variant, the proband’s mother and maternal grandmother are carriers and the maternal grandmother experienced unexplained syncope. The authors …
间隙连接蛋白 40 和连接蛋白 43 的空间分布和相对丰度与心脏房室传导系统各组成部分的功能特性相关。
影响因子：
4
作者：
Gourdie,RG;Severs,NJ;Green,CR;Rothery,S;Germroth,P;Thompson,RP
通讯作者：
Thompson,RP