Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.
Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.
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DOI：
10.1093/hmg/ddr470
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发表时间：
2012-01-15
影响因子：
3.5
通讯作者：
Rappold GA
中科院分区：
文献类型：
--
作者：
Berkel S;Tang W;Treviño M;Vogt M;Obenhaus HA;Gass P;Scherer SW;Sprengel R;Schratt G;Rappold GA
最近在自闭症谱系障碍（ASD）和智力残疾的个体中发现了突触后支架基因SHANK 2的突变。然而，神经元中这些突变的细胞和生理后果仍然未知。我们分析了ASD个体中两个遗传性和一个从头SHANK 2突变（L1008_P1009dup，T1127 M，R462 X）引起的功能影响。尽管所有三种变体都影响脊髓体积并且具有较小的SHANK 2簇大小，但T1127 M另外未能挽救Shank 2敲低神经元中的脊髓体积。R462 X不能挽救脊柱体积和树突分支，并且缺乏突触后聚集，表明最严重的功能障碍。为了证明R462 X在小鼠中表达时可以与生理效应相关，我们分析了突触传递和行为。表达rAAV转导的SHANK 2-R462 X的小鼠的主要神经元在微型突触后AMPA受体电流中呈现特异性的、持久的降低。这种显性负效应转化为SHANK 2-R462 X表达小鼠的剂量依赖性认知行为改变，对ASD的发病率产生影响。
Mutations in the postsynaptic scaffolding gene SHANK2 have recently been identified in individuals with autism spectrum disorder (ASD) and intellectual disability. However, the cellular and physiological consequences of these mutations in neurons remain unknown. We have analyzed the functional impact caused by two inherited and one de novo SHANK2 mutations from ASD individuals (L1008_P1009dup, T1127M, R462X). Although all three variants affect spine volume and have smaller SHANK2 cluster sizes, T1127M additionally fails to rescue spine volume in Shank2 knock-down neurons. R462X is not able to rescue spine volume and dendritic branching and lacks postsynaptic clustering, indicating the most severe dysfunction. To demonstrate that R462X when expressed in mouse can be linked to physiological effects, we analyzed synaptic transmission and behavior. Principal neurons of mice expressing rAAV-transduced SHANK2-R462X present a specific, long-lasting reduction in miniature postsynaptic AMPA receptor currents. This dominant negative effect translates into dose-dependent altered cognitive behavior of SHANK2-R462X-expressing mice, with an impact on the penetrance of ASD.
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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：
21.3
作者：
Siegel, Gabriele;Obernosterer, Gregor;Fiore, Roberto;Oehmen, Martin;Bicker, Silvia;Christensen, Mette;Khudayberdiev, Sharof;Leuschner, Philipp F.;Busch, Clara J. L.;Kane, Christina;Huebel, Katja;Dekker, Frank;Hedberg, Christian;Rengarajan, Balamurugan;Drepper, Carsten;Waldmann, Herbert;Kauppinen, Sakari;Greenberg, Michael E.;Draguhn, Andreas;Rehmsmeier, Marc;Martinez, Javier;Schratt, Gerhard M.
通讯作者：
Schratt, Gerhard M.
影响因子：
4.7
作者：
Boeckers, TM;Liedtke, T;Gundelfinger, ED
通讯作者：
Gundelfinger, ED
影响因子：
16.2
作者：
Naisbitt, S;Kim, E;Sheng, M
通讯作者：
Sheng, M
影响因子：
12.4
作者：
Smith, Richard H.;Levy, Justin R.;Kotin, Robert M.
通讯作者：
Kotin, Robert M.