Human Molecular Genetics
Abstract
Monogenic mutations in the SHANK3 gene, which encodes a postsynaptic scaffold protein, play a causative role in autism spectrum disorder (ASD). Although a number of mouse models with Shank3 mutations have been valuable for investigating the pathogenesis of ASD, species-dependent differences in behaviors and brain structures post considerable challenges to use small animals to model ASD and to translate experimental therapeutics to the clinic. We have used CRISPR/Cas9 to generate a cynomolgus monkey model by disrupting SHANK3 at exon 6 and 12. Analysis of the live mutant monkey revealed the core behavioral abnormalities of ASD, including impaired social interaction and repetitive behaviors, and reduced brain network activities detected by positron-emission tomography (PET). Importantly, these abnormal behaviors and brain activities were alleviated by the antidepressant fluoxetine treatment. Our findings provide the first demonstration that the genetically modified non-human primate can be used for translational research of therapeutics for ASD.
| 论文编号: | DOI:10.1093/hmg/ddy367 |
| 论文题目: | CRISPR/Cas9-mediated Disruption of SHANK3 in Monkey Leads to Drug-treatable Autism-like Symptoms |
| 英文论文题目: | CRISPR/Cas9-mediated Disruption of SHANK3 in Monkey Leads to Drug-treatable Autism-like Symptoms |
| 第一作者: | Zhuchi Tu, Hui Zhao, Bang Li, Sen Yan, Lu Wang, Yongjin Tang, Zhujun Li, Dazhang Bai, Caijuan Li, Yinqi Lin, Yuefeng Li, Jianrong Liu, Hao Xu, Xiangyu Guo, Yong-hui Jiang, Yong Q Zhang, Xiao-Jiang Li |
| 英文第一作者: | Zhuchi Tu, Hui Zhao, Bang Li, Sen Yan, Lu Wang, Yongjin Tang, Zhujun Li, Dazhang Bai, Caijuan Li, Yinqi Lin, Yuefeng Li, Jianrong Liu, Hao Xu, Xiangyu Guo, Yong-hui Jiang, Yong Q Zhang, Xiao-Jiang Li |
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| 发表年度: | 2018-10-18 |
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| 摘要: | Monogenic mutations in the SHANK3 gene, which encodes a postsynaptic scaffold protein, play a causative role in autism spectrum disorder (ASD). Although a number of mouse models with Shank3 mutations have been valuable for investigating the pathogenesis of ASD, species-dependent differences in behaviors and brain structures post considerable challenges to use small animals to model ASD and to translate experimental therapeutics to the clinic. We have used CRISPR/Cas9 to generate a cynomolgus monkey model by disrupting SHANK3 at exon 6 and 12. Analysis of the live mutant monkey revealed the core behavioral abnormalities of ASD, including impaired social interaction and repetitive behaviors, and reduced brain network activities detected by positron-emission tomography (PET). Importantly, these abnormal behaviors and brain activities were alleviated by the antidepressant fluoxetine treatment. Our findings provide the first demonstration that the genetically modified non-human primate can be used for translational research of therapeutics for ASD. |
| 英文摘要: | Monogenic mutations in the SHANK3 gene, which encodes a postsynaptic scaffold protein, play a causative role in autism spectrum disorder (ASD). Although a number of mouse models with Shank3 mutations have been valuable for investigating the pathogenesis of ASD, species-dependent differences in behaviors and brain structures post considerable challenges to use small animals to model ASD and to translate experimental therapeutics to the clinic. We have used CRISPR/Cas9 to generate a cynomolgus monkey model by disrupting SHANK3 at exon 6 and 12. Analysis of the live mutant monkey revealed the core behavioral abnormalities of ASD, including impaired social interaction and repetitive behaviors, and reduced brain network activities detected by positron-emission tomography (PET). Importantly, these abnormal behaviors and brain activities were alleviated by the antidepressant fluoxetine treatment. Our findings provide the first demonstration that the genetically modified non-human primate can be used for translational research of therapeutics for ASD. |
| 刊物名称: | Human Molecular Genetics |
| 英文刊物名称: | Human Molecular Genetics |
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| 其它备注: | Zhuchi Tu, Hui Zhao, Bang Li, Sen Yan, Lu Wang, Yongjin Tang, Zhujun Li, Dazhang Bai, Caijuan Li, Yinqi Lin, Yuefeng Li, Jianrong Liu, Hao Xu, Xiangyu Guo, Yong-hui Jiang, Yong Q Zhang, Xiao-Jiang Li. CRISPR/Cas9-mediated Disruption of SHANK3 in Monkey Leads to Drug-treatable Autism-like Symptoms. Human Molecular Genetics. DOI:10.1093/hmg/ddy367 |
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