A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation.
A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation.
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DOI：
10.1016/j.hrthm.2013.11.021
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发表时间：
2014-03
期刊：
影响因子：
5.5
通讯作者：
Delisle, Brian P.
中科院分区：
文献类型：
--
作者：
Bartos, Daniel C.;Giudicessi, John R.;Tester, David J.;Ackerman, Michael J.;Ohno, Seiko;Horie, Minoru;Gollob, Michael H.;Burgess, Don E.;Delisle, Brian P.
1型长QT综合征(LQT1)是由KCNQ1编码的Kv7.1通道功能缺失突变引起的，Kv7.1通道传导延迟整流钾电流(Iks)的缓慢激活成分。临床上，LQT1的诊断因表型表型的变化而变得复杂，大约25%的基因阳性个体存在隐藏的LQT1(静息校正的QT[QTC]间期≤为460ms)。以确定是否有特定的分子机制对隐匿性LQT1起作用。我们确认了一个多代LQT1家族，其中79%的P.Ile235Asn-KCNQ1(I235N-Kv7.1)基因阳性的患者隐藏了LQT1。我们通过体外分析和计算机模拟评估了I235N-Kv7.1对IKs和心室动作电位(AP)的影响。临床资料显示，10例I235N-Kv7.1患者在平板运动试验恢复期静息QT间期均正常，但QT间期延长异常。共表达野生型Kv7.1和I235N-Kv7.1(模仿患者基因)的HEK293细胞电压钳制显示，I235N-Kv7.1产生相对正常功能的Kv7.1通道，但对蛋白激酶A(PKA)激活不敏感。拟磷酸化和奎尼丁敏感性研究表明，I235N-Kv7.1限制了Kv7.1通道的构象变化，这是PKA磷酸化后上调iKs所必需的。计算室AP模拟预测，I235N-Kv7.1的PKA不敏感性是刺激β-肾上腺素能延长AP的主要原因，尤其是在较慢的周期长度。KCNQ1突变产生相对正常的Kv7.1通道，但通过PKA激活限制IKS的上调，可能导致隐藏的LQT1。
Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 channel that conducts the slowly activating component of the delayed rectifier K+ current (IKs). Clinically, the diagnosis of LQT1 is complicated by variable phenotypic expressivity, whereby approximately 25% of genotype-positive individuals present with concealed LQT1 (resting corrected QT [QTc] interval ≤ 460 ms). To determine whether a specific molecular mechanism contributes to concealed LQT1. We identified a multigenerational LQT1 family whereby 79% of the patients genotype-positive for p.Ile235Asn-KCNQ1 (I235N-Kv7.1) have concealed LQT1. We assessed the effect I235N-Kv7.1 has on IKs and the ventricular action potential (AP) by using in vitro analysis and computational simulations. Clinical data showed that all 10 patients with I235N-Kv7.1 have normal resting QTc intervals but abnormal QTc interval prolongation during the recovery phase of an electrocardiographic treadmill stress test. Voltage-clamping HEK293 cells coexpressing wild-type Kv7.1 and I235N-Kv7.1 (to mimic the patients’ genotypes) showed that I235N-Kv7.1 generated relatively normal functioning Kv7.1 channels but were insensitive to protein kinase A (PKA) activation. Phosphomimetic and quinidine sensitivity studies suggest that I235N-Kv7.1 limits the conformational changes in Kv7.1 channels, which are necessary to upregulate IKs after PKA phosphorylation. Computational ventricular AP simulations predicted that the PKA insensitivity of I235N-Kv7.1 is primarily responsible for prolonging the AP with β-adrenergic stimulation, especially at slower cycle lengths. KCNQ1 mutations that generate relatively normal Kv7.1 channels, but limit the upregulation of IKs by PKA activation, likely contribute to concealed LQT1.
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DOI：
10.1152/ajpheart.2000.279.6.h3003
发表时间：
2000-12-01
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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