Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.
Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.
复制标题
对非综合自闭症进行建模以及TRPC6破坏在人神经元中的影响。
DOI：
10.1038/mp.2014.141
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发表时间：
2015-11
影响因子：
11
通讯作者：
Muotri, A. R.
中科院分区：
文献类型：
--
作者：
Griesi-Oliveira, K.;Acab, A.;Gupta, A. R.;Sunaga, D. Y.;Chailangkarn, T.;Nicol, X.;Nunez, Y.;Walker, M. F.;Murdoch, J. D.;Sanders, S. J.;Fernandez, T. V.;Ji, W.;Lifton, R. P.;Vadasz, E.;Dietrich, A.;Pradhan, D.;Song, H.;Ming, G-I;Gu, X.;Haddad, G.;Marchetto, M. C. N.;Spitzer, N.;Passos-Bueno, M. R.;State, M. W.;Muotri, A. R.
越来越多的遗传变异与自闭症谱系障碍（ASD）有关，这些变异的功能研究对于阐明自闭症的病理生理学至关重要。在这里，我们报告了从头平衡易位TRPC6，阳离子通道，在非综合征型自闭症个体中断。使用多种模型，如牙髓细胞，iPSC衍生的神经元细胞和小鼠模型，我们证明TRPC 6减少或单倍不足导致神经元发育，形态和功能改变。观察到的神经元表型可以通过TRPC 6互补和IGF1或Hyperforin（一种TRPC 6特异性激动剂）治疗来挽救，这表明该途径发生改变的ASD个体可能从这些药物中受益。我们还证明了MeCP2水平影响TRPC6表达。MeCP2突变导致Rett综合征，揭示了ASD之间的共同途径。1041名ASD患者和2872名对照的TRPC6基因测序显示，ASD人群中有更多的非同义突变，并在两名患者中发现了功能缺失突变和不完全突变。总之，这些发现表明TRPC 6是ASD的一种新的易感基因，可能在多次打击模型中起作用。这是第一项使用iPSC衍生的人类神经元来模拟非综合征型ASD的研究，并说明了使用此类细胞模拟遗传复杂的散发性疾病的潜力。
An increasing number of genetic variants have been implicated in autism spectrum disorders (ASD), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, iPSC-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology, and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with IGF1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway might benefit from these drugs. We also demonstrate that MeCP2 levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.
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影响因子：
3.7
作者：
Chen J;Lin M;Foxe JJ;Pedrosa E;Hrabovsky A;Carroll R;Zheng D;Lachman HM
通讯作者：
Lachman HM
影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
3.3
作者：
Beltrao-Braga, Patricia C. B.;Pignatari, Graciela C.;Kerkis, Irina
通讯作者：
Kerkis, Irina
影响因子：
5.3
作者：
Dietrich, A;Schnitzler, MMY;Birnbaumer, L
通讯作者：
Birnbaumer, L