期刊
NATURE
卷 570, 期 7761, 页码 326-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1278-0
关键词
-
资金
- Broad Institute of MIT
- National Key R&D Program of China [2018YFA0107203, 2017YFA0103802]
- Shenzhen Overseas Innovation Team Project [KQTD20140630180249366]
- Guangdong Innovative and Entrepreneurial Research Team Program [2014ZT05S020]
- Frontier and Innovation of Key Technology Project in Science and Technology Department of Guangdong Province [2014B020225007, 2019B020235002]
- Program for New Century Excellent Talents in University of Ministry of Education of the People's Republic of China [NCET-12-1078]
- External Cooperation Program of Chinese Academy of Sciences [172644KYSB20160026]
- International Partnership Program of Chinese Academy of Sciences [172644KYS820170004, 172644KYSB20160175]
- Patrick J. McGovern Foundation
- Hundred Talent Program of Chinese Academy of Sciences [81425016, 31671119]
- Shenzhen Science and Technology Innovation Commission [JCYJ20151030140325151, GJHZ20160229200136090, JCYJ20170413165053031, JCYJ20170413162938668]
- Simons Center for the Social Brain at MIT and Nancy Lurie Marks Family Foundation
- McGovern Institute for Brain Research at MIT
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior [2017B030301017]
- Shenzhen Discipline Construction Project for Neurobiology [DRCSM [2016]1379]
- Shenzhen-Hong Kong Institute of Brain Science
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 Phelan-McDermid 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 CRISPR-Cas9-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 Phelan-McDermid syndrome.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据