Atypical behaviour and connectivity in SHANK3-mutant macaques

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 () and Shihua Yang ()
Additional contact information
Yang Zhou: Chinese Academy of Sciences
Jitendra Sharma: Massachusetts Institute of Technology
Qiong Ke: Sun Yat-Sen University
Rogier Landman: Massachusetts Institute of Technology
Jingli Yuan: South China Agricultural University
Hong Chen: Sun Yat-Sen University
David S. Hayden: Massachusetts Institute of Technology
John W. Fisher: Massachusetts Institute of Technology
Minqing Jiang: Chinese Academy of Sciences
William Menegas: Massachusetts Institute of Technology
Tomomi Aida: Massachusetts Institute of Technology
Ting Yan: Chinese Academy of Sciences
Ying Zou: Chinese Academy of Sciences
Dongdong Xu: Chinese Academy of Sciences
Shivangi Parmar: Massachusetts Institute of Technology
Julia B. Hyman: Massachusetts Institute of Technology
Adrian Fanucci-Kiss: Massachusetts Institute of Technology
Olivia Meisner: Massachusetts Institute of Technology
Dongqing Wang: Massachusetts Institute of Technology
Yan Huang: South China Agricultural University
Yaqing Li: South China Agricultural University
Yanyang Bai: Chinese Academy of Sciences
Wenjing Ji: Chinese Academy of Sciences
Xinqiang Lai: Sun Yat-Sen University
Weiqiang Li: Sun Yat-Sen University
Lihua Huang: Sun Yat-Sen University
Zhonghua Lu: Chinese Academy of Sciences
Liping Wang: Chinese Academy of Sciences
Sheeba A. Anteraper: Massachusetts Institute of Technology
Mriganka Sur: Massachusetts Institute of Technology
Huihui Zhou: Chinese Academy of Sciences
Andy Peng Xiang: Sun Yat-Sen University
Robert Desimone: Massachusetts Institute of Technology
Guoping Feng: Massachusetts Institute of Technology
Shihua Yang: South China Agricultural University

Nature, 2019, vol. 570, issue 7761, 326-331

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1278-0

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