Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia
Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia
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DOI：
10.1161/circulationaha.106.623793
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发表时间：
2006-09-05
期刊：
影响因子：
37.8
通讯作者：
Priori, Silvia G.
中科院分区：
文献类型：
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作者：
di Barletta, Marina Raffaele;Viatchenko-Karpinski, Serge;Priori, Silvia G.
背景-人类心脏钙螯合蛋白基因（CASQ 2）的四种不同突变与儿茶酚胺能多态性室性心动过速（CPVT）有关。导致临床表型的机制仍然知之甚少，因为只有1 CASQ 2突变已被表征在vitro.Methods和Results -我们确定了一个纯合的16-bp缺失在位置339至354导致移码和终止密码子后5aa（CASQ 2（G112+5X））在一个孩子与应激诱导的室性心动过速和心脏骤停。同样的缺失也与一个高度症状性CPVT儿童的新点突变（CASQ 2（L167 H））相关，该儿童是第一个复合杂合CASQ 2突变的CPVT患者携带者。我们在体外表征了CASQ 2突变体的性质：CASQ 2（G112+5X）不结合Ca 2+，而CASQ 2（L167 H）具有正常的钙结合性质。当在大鼠心肌细胞中表达时，这两种突变体降低了肌浆网Ca 2+储存能力，并降低了I-Ca诱导的Ca 2+瞬变和透化心肌细胞中自发Ca 2+火花的幅度。结论：CASQ 2（L167 H）和CASQ 2（G112 + 5X）可改变CASQ 2的功能，导致心肌细胞活性肌浆网Ca ~（2+）释放减少和钙含量减少。此外，CASQ 2（G112+5X）显示出改变的钙结合特性，并导致延迟后去极化。我们的结论是，在CPVT中发现的2个CASQ 2突变产生了导致细胞内钙调节异常的明显异常，从而促进了快速性心律失常的发展。
Background - Four distinct mutations in the human cardiac calsequestrin gene (CASQ2) have been linked to catechol-aminergic polymorphic ventricular tachycardia (CPVT). The mechanisms leading to the clinical phenotype are still poorly understood because only 1 CASQ2 mutation has been characterized in vitro.Methods and Results - We identified a homozygous 16-bp deletion at position 339 to 354 leading to a frame shift and a stop codon after 5aa (CASQ2(G112+5X)) in a child with stress-induced ventricular tachycardia and cardiac arrest. The same deletion was also identified in association with a novel point mutation (CASQ2(L167H)) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations. We characterized in vitro the properties of CASQ2 mutants: CASQ2(G112+5X) did not bind Ca2+, whereas CASQ2(L167H) had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity and reduced the amplitude of I-Ca-induced Ca2+ transients and of spontaneous Ca2+ sparks in permeabilized myocytes. Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X).Conclusions - CASQ2(L167H) and CASQ2(G112+5X) alter CASQ2 function in cardiac myocytes, which leads to reduction of active sarcoplasmic reticulum Ca2+ release and calcium content. In addition, CASQ2(G112+5X) displays altered calcium-binding properties and leads to delayed afterdepolarizations. We conclude that the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias.