SHANK3（編碼SHANK3突觸支架蛋白的基因）發(fā)生的突變與自閉癥,、智殘和精神分裂癥有關(guān)，但SHANK3過(guò)度表達(dá)的效應(yīng)卻不大清楚,。
現(xiàn)在,，Huda Zoghbi及同事發(fā)現(xiàn)，過(guò)度表達(dá)Shank3的小鼠會(huì)表現(xiàn)出類(lèi)似狂躁的行為以及癲癇發(fā)作和神經(jīng)活動(dòng)的激發(fā)/抑制平衡發(fā)生改變等,。與在小鼠身上的這些發(fā)現(xiàn)相一致的是,，他們識(shí)別出了在22號(hào)染色體上攜帶含SHANK3區(qū)域的一個(gè)基因復(fù)本的兩個(gè)多動(dòng)癥患者,。
這些發(fā)現(xiàn)支持以下假設(shè)：任何一個(gè)方向上（過(guò)度表達(dá)和表達(dá)不足）的不正確基因劑量都可能是有害的,。作者提出，這項(xiàng)研究中所用的小鼠為了解某些形式的躁郁癥的藥物遺傳機(jī)理提供了一個(gè)模型,。（生物谷Bioon.com）
生物谷推薦的英文摘要
Nature doi:10.1038/nature12630
SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties
Kihoon Han,，J. Lloyd Holder Jr，Christian P. Schaaf,，Hui Lu,，Hongmei Chen，Hyojin Kang，Jianrong Tang,，Zhenyu Wu,，Shuang Hao，Sau Wai Cheung,，Peng Yu,，Hao Sun，Amy M. Breman,，Ankita Patel,，Hui-Chen Lu& Huda Y. Zoghbi
Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders， indicating that proper SHANK3 dosage is critical for normal brain function. However,， SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype,， we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate， but not lithium,， rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
