SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.
SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.
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DOI：
10.1038/mp.2011.57
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发表时间：
2012-01
影响因子：
11
通讯作者：
Sans N
中科院分区：
文献类型：
--
作者：
Durand CM;Perroy J;Loll F;Perrais D;Fagni L;Bourgeron T;Montcouquiol M;Sans N
在智力残疾、自闭症谱系障碍（ASD）和精神分裂症患者中已报道了SHANK3的基因突变。在突触处，Shank3/ProSAP2是一种支架蛋白，它通过一系列中间元件将谷氨酸受体连接到肌动蛋白细胞骨架上。尽管遗传学研究已反复证实SHANK3突变与精神疾病易感性相关，但对于这些突变在神经元方面的影响知之甚少。在此，我们报告了在自闭症患者中发现的两种新生突变（终止密码子突变和Q321R突变）以及两种遗传变异（R12C和R300C）的功能影响。我们发现Shank3位于肌动蛋白丝的末端并增强其聚合作用。Shank3还参与发育中神经元的生长锥运动。截短突变（终止密码子突变）强烈影响树突棘的发育和形态，减少成熟神经元中的突触传递，并且还抑制Shank3对生长锥运动的作用。锚蛋白结构域中的新生突变（Q321R）改变了Shank3在棘诱导和形态以及棘中肌动蛋白积累方面的作用，并影响生长锥运动。最后，两种遗传突变（R12C和R300C）对棘密度和突触传递具有中等程度的影响。因此，尽管这些突变由健康的父母遗传而来，但它们的功能影响强烈表明它们可能是自闭症的风险因素。总之，这些数据为人类中SHANK3突变引起的突触改变提供了新的见解，并为基于知识的治疗方法的开发提供了可靠的细胞层面的解读。
Genetic mutations of SHANK3 have been reported in patients with intellectual disability, autism spectrum disorder (ASD) and schizophrenia. At the synapse, Shank3/ProSAP2 is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements. Although genetic studies have repeatedly confirmed the association of SHANK3 mutations with susceptibility to psychiatric disorders, very little is known about the neuronal consequences of these mutations. Here, we report the functional effects of two de novo mutations (STOP and Q321R) and two inherited variations (R12C and R300C) identified in patients with ASD. We show that Shank3 is located at the tip of actin filaments and enhances its polymerization. Shank3 also participates in growth cone motility in developing neurons. The truncating mutation (STOP) strongly affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility. The de novo mutation in the ankyrin domain (Q321R) modifies the roles of Shank3 in spine induction and morphology, and actin accumulation in spines and affects growth cone motility. Finally, the two inherited mutations (R12C and R300C) have intermediate effects on spine density and synaptic transmission. Therefore, although inherited by healthy parents, the functional effects of these mutations strongly suggest that they could represent risk factors for ASD. Altogether, these data provide new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies.
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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：
64.8
作者：
Cook, Edwin H., Jr.;Scherer, Stephen W.
通讯作者：
Scherer, Stephen W.
影响因子：
4.7
作者：
Boeckers, TM;Liedtke, T;Gundelfinger, ED
通讯作者：
Gundelfinger, ED
影响因子：
5.3
作者：
Grove, M;Demyanenko, G;Pendergast, AM
通讯作者：
Pendergast, AM
影响因子：
5.3
作者：
Hung, Albert Y.;Futai, Kensuke;Sheng, Morgan
通讯作者：
Sheng, Morgan