华南农业大学杨世华课题组发现了Shank3基因突变猕猴的非典型行为和异常的脑部结构连接。 这一研究成果发表在2019年6月20日出版的国际学术期刊《自然》杂志上。

本研究利用CRISPR-Cas9基因编辑系统，介导了食蟹猕猴及其后代SHANK3的种系传代突变。通过对体细胞和脑部活检组织进行基因分型，验证了这些猕猴SHANK3基因发生突变，同时SHANK3蛋白表达水平降低。功能性磁共振成像数据显示突变体猕猴脑部局部和整体连接模式发生改变，提示脑电波异常。首代突变体个体表现出睡眠障碍、运动障碍、重复性行为增加，以及社交和学习障碍的症状。总的来说，这些结果与SHANK3基因和回路功能障碍的某些方面相互印证，也与其行为表型相一致，而这些研究结果正是代表了自闭症谱系障碍和斐兰-麦克德米德综合征(即，22q13.3缺失综合征)的特征。

研究人员表示，SH3和SHANK3基因的突变或缺失是自闭症谱系障碍的一种高外显率单基因危险因素，也是斐兰-麦克德米德综合征的原因之一。最近在基因编辑方面的进展使非人类灵长类动物基因工程模型的建立成为可能，这可能比利用啮齿动物模型更接近人类自闭症谱系障碍的行为和神经表型，并可能介导更有效的治疗。

附：英文原文

Title: Atypical behaviour and connectivity in SHANK3 -mutant macaques

Author: Yang Zhou, Jitendra Sharma, Qiong Ke, Rogier Landman, Jingli Yuan, Hong Chen, David S. Hayden, John W. Fisher, Minqing Jiang, William Menegas, Tomomi Aida, Ting Yan, Ying Zou, Dongdong Xu, Shivangi Parmar, Julia B. Hyman, Adrian Fanucci-Kiss, Olivia Meisner, Dongqing Wang, Yan Huang, Yaqing Li, Yanyang Bai, Wenjing Ji, Xinqiang Lai, Weiqiang Li, Lihua Huang, Zhonghua Lu, Liping Wang, Sheeba A. Anteraper, Mriganka Sur, Huihui Zhou, Andy Peng Xiang, Robert Desimone, Guoping Feng, Shihua Yang

Issue&Volume: Volume 570 Issue 7761, 20 June 2019

Abstract: Mutation or disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of PhelanMcDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPRCas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3 gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and PhelanMcDermid syndrome.

DOI: 10.1038/s41586-019-1278-0

Source: https://www.nature.com/articles/s41586-019-1278-0