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Nature. 2019 Jun;570(7761):326-331. doi: 10.1038/s41586-019-1278-0. Epub 2019 Jun 12.

Atypical behaviour and connectivity in SHANK3-mutant macaques.

Author information

1
Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
2
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
3
Montreal Neurological Institute & Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
4
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
5
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
6
Simons Center for the Social Brain, Massachusetts Institute of Technology, Cambridge, MA, USA.
7
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
8
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-Sen University, Guangzhou, China.
9
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
10
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
11
College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
12
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
13
Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. hh.zhou@siat.ac.cn.
14
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
15
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. xiangp@mail.sysu.edu.cn.
16
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. fengg@mit.edu.
17
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. fengg@mit.edu.
18
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. fengg@mit.edu.
19
College of Veterinary Medicine, South China Agricultural University, Guangzhou, China. yangsh@scau.edu.cn.

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 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.

PMID:
31189958
DOI:
10.1038/s41586-019-1278-0

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