A human Dravet syndrome model from patient induced pluripotent stem cells.
A human Dravet syndrome model from patient induced pluripotent stem cells.
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DOI：
10.1186/1756-6606-6-19
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发表时间：
2013-05-02
期刊：
影响因子：
3.6
通讯作者：
Hirose S
中科院分区：
文献类型：
--
作者：
Higurashi N;Uchida T;Lossin C;Misumi Y;Okada Y;Akamatsu W;Imaizumi Y;Zhang B;Nabeshima K;Mori MX;Katsurabayashi S;Shirasaka Y;Okano H;Hirose S
Dravet综合征是一种毁灭性的癫痫发作综合征，具有认知缺陷和自闭症特征，由编码电压门控钠通道Nav1.1 α亚基的SCN 1A基因的遗传改变引起。使用患者来源的诱导多能干细胞（iPSC）进行疾病建模可以成为复制这种综合征的人类病理学的有力工具。然而，迄今为止没有关于这方面努力的报告。我们在这里报告了一种利用患者来源的iPSC的DS细胞模型。我们从Dravet综合征患者中产生了在SCN 1A中具有c.4933C>T取代的iPSC，预测其导致蛋白质的第四同源结构域（p.R1645*）的截短。来源于这些iPSC的神经元主要是GABA能的（>50%），尽管观察到GABA能神经元作为少数群体（<1%）。电流钳分析显示，当注入强去极化电流时，动作电位产生显著受损。我们的研究结果表明Dravet神经元的功能下降，特别是在GABA能亚型中，这支持了先前在小鼠疾病模型中的发现，其中GABA能抑制的功能丧失似乎是癫痫发生的主要驱动因素。我们的数据表明，患者来源的iPSCs可以作为一个新的和强大的研究平台，遗传性疾病，包括癫痫。
Dravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the α-subunit of the voltage-gated sodium channel Nav1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndrome’s human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs. We generated iPSCs from a Dravet syndrome patient with a c.4933C>T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (>50%), although glutamatergic neurons were observed as a minor population (<1%). Current-clamp analyses revealed significant impairment in action potential generation when strong depolarizing currents were injected. Our results indicate a functional decline in Dravet neurons, especially in the GABAergic subtype, which supports previous findings in murine disease models, where loss-of-function in GABAergic inhibition appears to be a main driver in epileptogenesis. Our data indicate that patient-derived iPSCs may serve as a new and powerful research platform for genetic disorders, including the epilepsies.
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DOI：
10.1126/science.1187958
发表时间：
2010-05-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lorincz A;Nusser Z
通讯作者：
Nusser Z
影响因子：
4.4
作者：
Martin, Melinda S.;Tang, Bin;Escayg, Andrew
通讯作者：
Escayg, Andrew
DOI：
10.1073/pnas.0501263102
发表时间：
2005-04-12
影响因子：
11.1
作者：
Amoh, Y;Li, L;Hoffman, RM
通讯作者：
Hoffman, RM
影响因子：
3.7
作者：
Gulacsi, Alexandra;Anderson, Stewart A.
通讯作者：
Anderson, Stewart A.
影响因子：
5.6
作者：
Bechi, Giulia;Scalmani, Paolo;Mantegazza, Massimo
通讯作者：
Mantegazza, Massimo