Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.
Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.
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DOI：
10.1038/nature09855
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发表时间：
2011-03-10
期刊：
影响因子：
64.8
通讯作者：
Dolmetsch, Ricardo E.
中科院分区：
文献类型：
--
作者：
Yazawa, Masayuki;Hsueh, Brian;Jia, Xiaolin;Pasca, Anca M.;Bernstein, Jonathan A.;Hallmayer, Joachim;Dolmetsch, Ricardo E.
患有先天性或获得性QT间期延长或长QT综合征（LQTS）的个体有发生危及生命的室性心律失常的风险。LQTS通常是遗传性的，但也可以由环境因素引起或加剧。Timothy综合征（TS）患者L型钙通道CaV1.2错义突变导致LQTS为了探索TS突变对人类心肌细胞（CM）电活动和收缩的影响，我们重新编程了TS患者的人类皮肤细胞以产生诱导多能干细胞（iPSC），并将这些细胞分化为CM。这些细胞的电生理记录和钙（Ca 2+）成像研究显示不规则的收缩，过量的Ca 2+内流，延长动作电位，不规则的电活动和异常的钙瞬变的心室样细胞。我们发现，roscovitine（Ros），一种增加CaV1.2的电压依赖性失活的化合物，恢复了TS患者CM的电和Ca2+信号传导特性。这项研究为研究人类心律失常的分子和细胞机制开辟了新的途径，并为开发治疗这些疾病的新药提供了可靠的检测方法。
Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel CaV1.2 leads to LQTS in patients with Timothy syndrome (TS). To explore the effect of the TS mutation on the electrical activity and contraction of human cardiomyocytes (CMs), we reprogrammed human skin cells from TS patients to generate induced pluripotent stem cells (iPSCs), and differentiated these cells into CMs. Electrophysiological recording and calcium (Ca2+) imaging studies of these cells revealed irregular contraction, excess Ca2+ influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine (Ros), a compound that increases the voltage-dependent inactivation (VDI) of CaV1.2, restored the electrical and Ca2+ signaling properties of CMs from TS patients. This study opens new avenues for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.
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DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
影响因子：
20.1
作者：
Zhang J;Wilson GF;Soerens AG;Koonce CH;Yu J;Palecek SP;Thomson JA;Kamp TJ
通讯作者：
Kamp TJ
影响因子：
5.2
作者：
Tran, Thanh H.;Wang, Xiurong;Burcin, Mark
通讯作者：
Burcin, Mark
DOI：
10.1073/pnas.0710527105
发表时间：
2007-12-26
影响因子：
11.1
作者：
Chen, Lei;Marquardt, Michelle L.;Kass, Robert S.
通讯作者：
Kass, Robert S.
影响因子：
56.9
作者：
Yu, Junying;Vodyanik, Maxim A.;Thomson, James A.
通讯作者：
Thomson, James A.