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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutation of an A-kinase-anchoring protein causes Iong-QT syndrome
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Mutation of an A-kinase-anchoring protein causes Iong-QT syndrome

机译：锚定A激酶的蛋白突变导致Long-QT综合征

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摘要

A-kinase anchoring proteins (AKAPs) recruit signaling molecules and present them to downstream targets to achieve efficient spatial and temporal control of their phosphorylation state. In the heart, sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD), mediated by β-adrenergic receptor (J3AR) activation, requires assembly of AKAP9 (Yotiao) with the l_(Ks) potassium channel a subunit (KCNQ1). KCNQ1 mutations that disrupt this complex cause type 1 long-QT syndrome (LQT1), one of the potentially lethal heritable arrhythmia syndromes. Here, we report identification of (ⅰ) regions on Yotiao critical to its binding to KCNQ1 and (ⅱ) a single putative LQTS-causing mutation (S1570L) in AKAP9 (Yotiao) localized to the KCNQ1 binding domain in 1/50 (2%) subjects with a clinically robust phenotype for LQTS but absent in 1,320 reference alleles. The inherited S1570L mutation reduces the interaction between KCNQ1 and Yotiao, reduces the cAMP-induced phosphorylation of the channel, eliminates the functional response of the I_(Ks) channel to cAMP, and prolongs the action potential in a computational model of the ventricular cardiocyte. These reconstituted cellular consequences of the inherited S1570L-Yotiao mutation are consistent with delayed repolar-ization of the ventricular action potential observed in the affected siblings. Thus, we have demonstrated a link between genetic perturbations in AKAP and human disease in general and AKAP9 and LQTS in particular.
机译：A激酶锚定蛋白（AKAP）募集信号分子并将其呈递给下游靶标，以实现对其磷酸化状态的有效时空控制。在心脏中，由β-肾上腺素能受体（J3AR）激活介导的交感神经系统（SNS）对心脏动作电位持续时间（APD）的调节，要求组装带有L_（Ks）钾通道一个亚基（KCNQ1）的AKAP9（Yotiao）。 ）。破坏此复杂结构的KCNQ1突变会导致1型长QT综合征（LQT1），这是一种可能致命的遗传性心律失常综合征。在这里，我们报告鉴定（1）鉴定在Yotiao上对其结合KCNQ1至关重要的区域，以及（ⅱ）在AKAP9（Yotiao）中单个推定的LQTS致突变（S1570L）定位于KCNQ1结合域的1/50（2％ ）具有LQTS临床稳固表型但在1,320个参考等位基因中不存在的受试者。遗传的S1570L突变减少了KCNQ1和Yotiao之间的相互作用，减少了cAMP诱导的通道磷酸化，消除了I_（Ks）通道对cAMP的功能响应，并延长了心室心肌细胞计算模型中的动作电位。遗传的S1570L-Yotiao突变的这些重组细胞后果与在受影响的兄弟姐妹中观察到的心室动作电位的延迟复极化是一致的。因此，我们已经证明了AKAP的遗传扰动和一般人类疾病之间的联系，尤其是AKAP9和LQTS。

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