Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia
Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia
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DOI：
10.1161/01.cir.103.4.485
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发表时间：
2001-01-30
期刊：
影响因子：
37.8
通讯作者：
Kontula, K
中科院分区：
文献类型：
--
作者：
Laitinen, PJ;Brown, KM;Kontula, K
家族性多形性室性心动过速是一种常染色体显性遗传性疾病，发病相对较早，30岁以下死亡率约为30%。其表型特征是剧烈运动时出现一系列双向和多形性室性心动过速，无心肌疾病的结构性证据。我们先前将致病基因定位于染色体1 q42-q43。在本研究中，我们证明了家族性多形性室性心动过速患者在心肌肌浆网钙释放通道（Ryanodine受体2型[RyR 2]）中存在错义突变。方法和结果-在3个研究的大家族中，检测到3种不同的RyR 2突变（P2328 S，Q4201 R，V4653 F），并显示与特征性室性心动过速表型完全共分离。这些突变在未受影响的家庭成员和100名健康对照中不存在。除了确定3个致病突变，我们确定了一些单核苷酸多态性，跨越RyR 2的基因组结构，将是有用的候选人为基础的关联研究为其他mammic disorders.Conclusions-Our的数据说明，RyR 2基因的突变导致至少一种遗传性多态性心动过速。这些发现定义了一个新的实体的心肌钙信号障碍。
Background-Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximate to 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]).Methods and Results-In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders.Conclusions-Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.