Mutation of an A-kinase-anchoring protein causes long-QT syndrome
Mutation of an A-kinase-anchoring protein causes long-QT syndrome
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DOI：
10.1073/pnas.0710527105
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发表时间：
2007-12-26
影响因子：
11.1
通讯作者：
Kass, Robert S.
中科院分区：
文献类型：
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作者：
Chen, Lei;Marquardt, Michelle L.;Kass, Robert S.
A激酶锚定蛋白（AKAP）募集信号分子并将其呈递给下游靶点，以实现对其磷酸化状态的有效空间和时间控制。在心脏中，由β-肾上腺素能受体（PAR）激活介导的心脏动作电位时程（APD）的交感神经系统（CHD）调节需要AKAP 9（Yotiao）与I-Ks钾通道α亚基（KCNQ 1）的组装。KCNQ 1突变破坏了这种复合物，导致1型长QT综合征（LQT 1），这是一种潜在致命的遗传性心律失常综合征。在这里，我们报告了鉴定（i）Yotiao上与KCNQ 1结合的关键区域，以及（ii）AKAP 9（Yotiao）中定位于KCNQ 1结合结构域的单一推定LQTS引起突变（S1 570 L），这些突变在1/50（2%）具有临床稳健LQTS表型但在1，320个参考等位基因中不存在的受试者中存在。遗传性S1570 L突变减少了KCNQ 1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的功能反应，并在心室心肌细胞的计算模型中抑制了动作电位。遗传性S1570 L-Yotiao突变的这些重建细胞结果与在受影响的兄弟姐妹中观察到的心室动作电位复极延迟一致。因此，我们已经证明了AKAP中的遗传扰动与人类疾病之间的联系，特别是AKAP 9和LQTS。
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 (SINS) regulation of cardiac action potential duration (APD), mediated by P-adrenergic receptor (PAR) activation, requires assembly of AKAP9 (Yotiao) with the I-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 (it) a single putative LQTS-causing mutation (S1 570L) 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 repolarization 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.