Chen Yongchang, Yu Juehua, Niu Yuyu, Qin Dongdong, Liu Hailiang, Li Gang, Hu Yingzhou, Wang Jiaojian, Lu Yi, Kang Yu, Jiang Yong, Wu Kunhua, Li Siguang, Wei Jingkuan, He Jing, Wang Junbang, Liu Xiaojing, Luo Yuping, Si Chenyang, Bai Raoxian, Zhang Kunshan, Liu Jie, Huang Shaoyong, Chen Zhenzhen, Wang Shuang, Chen Xiaoying, Bao Xinhua, Zhang Qingping, Li Fuxing, Geng Rui, Liang Aibin, Shen Dinggang, Jiang Tianzi, Hu Xintian, Ma Yuanye, Ji Weizhi, Sun Yi Eve
Yunnan Key Laboratory of Primate Biomedicine Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China; Yunnan Provincial Academy of Science and Technology, Kunming 650051, China; Kunming Enovate Institute of Bioscience, Kunming 650000, China.
Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Cell. 2017 May 18;169(5):945-955.e10. doi: 10.1016/j.cell.2017.04.035.
Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.
基因编辑技术已使创建用于人类遗传疾病的非人灵长类动物模型成为可能。在此，我们报告了经TALEN编辑的MECP2突变食蟹猴的详细基因型和表型，这些猴子作为一种神经发育障碍——雷特综合征（RTT）的模型，该疾病由人类MECP2基因的功能丧失突变引起。雄性突变猴胚胎致死，再次表明RTT是一种女性疾病。通过一系列行为分析，包括灵长类动物特有的眼动追踪测试，并结合通过MRI进行的脑成像，我们发现了一系列类似于RTT临床表现的生理、行为和结构异常。此外，血液转录组分析表明，突变猴在免疫基因失调方面与RTT患者相似。综上所述，猴子与患者在表型和/或内表型上的明显相似性表明，基因编辑的RTT奠基猴对于疾病机制研究以及RTT潜在治疗干预措施的开发具有价值。
