A cardiac arrhythmia syndrome caused by loss of ankyrin-B function
A cardiac arrhythmia syndrome caused by loss of ankyrin-B function
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DOI：
10.1073/pnas.0402546101
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发表时间：
2004-06-15
影响因子：
11.1
通讯作者：
Bennett, V
中科院分区：
文献类型：
--
作者：
Mohler, PJ;Splawski, I;Bennett, V
220-kDa锚蛋白b是在心肌细胞横小管/肌浆网位点协调组装Na/Ca交换器、Na/K ATIPase和肌醇三磷酸（InsP(3)）受体所必需的。在一个扩展亲属中发现的锚蛋白b的功能丧失突变导致主要遗传性心律失常，最初被描述为4型长QT综合征。在这里，我们报告了8个不相关的含有锚蛋白b功能丧失突变的先发基因的鉴定，包括4个先前描述的突变，其临床特征将与锚蛋白b活性丧失相关的心脏表型与经典的长QT综合征区分开来。具有栓蛋白b突变的人表现出不同程度的心功能障碍，包括心动过缓、窦性心律失常、特发性心室颤动、儿茶酚胺能多形性室性心动过速和猝死风险。然而，经速率校正的QT间期延长并不是一个一致的特征，这表明锚蛋白b功能障碍是一种不同于经典长QT综合征的临床特征。突变定位于锚蛋白b调控结构域，这是心肌细胞中锚蛋白b和锚蛋白g功能的区别。所有突变都取消了锚蛋白b恢复异常Ca2+动力学和Na/Ca交换器、Na/K atp酶和lnsP(3)R在wankyrin-B+/-心肌细胞中的异常定位和表达的能力。这项研究，考虑到与心脏功能障碍相关的锚蛋白b突变的首次描述，支持先前描述的人类疾病的模式，由于多种功能相关的离子通道和转运体的异常协调，在这种情况下，Na/K ATIPase， Na/Ca交换器和InsP3受体。
220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATIPase, and inositol trisphosphate (InsP(3)) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardionnyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca2+ dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and lnsP(3)R in wankyrin-B+/- cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na/K ATIPase, Na/Ca exchanger, and InsP3 receptor.