Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Yongchang Chen; Juehua Yu; Yuyu Niu; Dongdong Qin; Hailiang Liu; Gang Li; Yingzhou Hu; Jiaojian Wang; Yi Lu; Yu Kang; Yong Jiang; Kunhua Wu; Siguang Li; Jingkuan Wei; Jing He; Junbang Wang; Xiaojing Liu; Yuping Luo; Chenyang Si; Raoxian Bai; Kunshan Zhang; Jie Liu; Shaoyong Huang; Zhenzhen Chen; Shuang Wang; Xiaoying Chen; Xinhua Bao; Qingping Zhang; Fuxing Li; Rui Geng; Aibin Liang; Dinggang Shen; Tianzi Jiang; Xintian Hu; Yuanye Ma; Weizhi Ji; Yi Eve Sun

doi:10.1016/j.cell.2017.04.035

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Yongchang Chen, Juehua Yu, Yuyu Niu, Dongdong Qin, Hailiang Liu, Gang Li, Yingzhou Hu, Jiaojian Wang, Yi Lu, Yu Kang, Yong Jiang, Kunhua Wu, Siguang Li, Jingkuan Wei, Jing He, Junbang Wang, Xiaojing Liu, Yuping Luo, Chenyang Si, Raoxian BaiKunshan Zhang, Jie Liu, Shaoyong Huang, Zhenzhen Chen, Shuang Wang, Xiaoying Chen, Xinhua Bao, Qingping Zhang, Fuxing Li, Rui Geng, Aibin Liang, Dinggang Shen, Tianzi Jiang, Xintian Hu, Yuanye Ma, Weizhi Ji, Yi Eve Sun

Hope Center for Neurological Disorders

Research output: Contribution to journal › Article › peer-review

164 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	945-955.e10
Journal	Cell
Volume	169
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2017.04.035
State	Published - May 18 2017

Keywords

MECP2
Rett syndrome
disease models
gene editing
male embryonic lethal
neurodevelopmental disorder
non-human primate

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10.1016/j.cell.2017.04.035

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@article{3d86b37ee01341a98127170cae46a1d5,

title = "Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys",

abstract = "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.",

keywords = "MECP2, Rett syndrome, disease models, gene editing, male embryonic lethal, neurodevelopmental disorder, non-human primate",

author = "Yongchang Chen and Juehua Yu and Yuyu Niu and Dongdong Qin and Hailiang Liu and Gang Li and Yingzhou Hu and Jiaojian Wang and Yi Lu and Yu Kang and Yong Jiang and Kunhua Wu and Siguang Li and Jingkuan Wei and Jing He and Junbang Wang and Xiaojing Liu and Yuping Luo and Chenyang Si and Raoxian Bai and Kunshan Zhang and Jie Liu and Shaoyong Huang and Zhenzhen Chen and Shuang Wang and Xiaoying Chen and Xinhua Bao and Qingping Zhang and Fuxing Li and Rui Geng and Aibin Liang and Dinggang Shen and Tianzi Jiang and Xintian Hu and Yuanye Ma and Weizhi Ji and Sun, {Yi Eve}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = may,

day = "18",

doi = "10.1016/j.cell.2017.04.035",

language = "English",

volume = "169",

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journal = "Cell",

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Chen, Y, Yu, J, Niu, Y, Qin, D, Liu, H, Li, G, Hu, Y, Wang, J, Lu, Y, Kang, Y, Jiang, Y, Wu, K, Li, S, Wei, J, He, J, Wang, J, Liu, X, Luo, Y, Si, C, Bai, R, Zhang, K, Liu, J, Huang, S, Chen, Z, Wang, S, Chen, X, Bao, X, Zhang, Q, Li, F, Geng, R, Liang, A, Shen, D, Jiang, T, Hu, X, Ma, Y, Ji, W & Sun, YE 2017, 'Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys', Cell, vol. 169, no. 5, pp. 945-955.e10. https://doi.org/10.1016/j.cell.2017.04.035

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T1 - Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

AU - Chen, Yongchang

AU - Yu, Juehua

AU - Niu, Yuyu

AU - Qin, Dongdong

AU - Liu, Hailiang

AU - Li, Gang

AU - Hu, Yingzhou

AU - Wang, Jiaojian

AU - Lu, Yi

AU - Kang, Yu

AU - Jiang, Yong

AU - Wu, Kunhua

AU - Li, Siguang

AU - Wei, Jingkuan

AU - He, Jing

AU - Wang, Junbang

AU - Liu, Xiaojing

AU - Luo, Yuping

AU - Si, Chenyang

AU - Bai, Raoxian

AU - Zhang, Kunshan

AU - Liu, Jie

AU - Huang, Shaoyong

AU - Chen, Zhenzhen

AU - Wang, Shuang

AU - Chen, Xiaoying

AU - Bao, Xinhua

AU - Zhang, Qingping

AU - Li, Fuxing

AU - Geng, Rui

AU - Liang, Aibin

AU - Shen, Dinggang

AU - Jiang, Tianzi

AU - Hu, Xintian

AU - Ma, Yuanye

AU - Ji, Weizhi

AU - Sun, Yi Eve

PY - 2017/5/18

Y1 - 2017/5/18

N2 - 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.

AB - 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.

KW - MECP2

KW - Rett syndrome

KW - disease models

KW - gene editing

KW - male embryonic lethal

KW - neurodevelopmental disorder

KW - non-human primate

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U2 - 10.1016/j.cell.2017.04.035

DO - 10.1016/j.cell.2017.04.035

M3 - Article

C2 - 28525759

AN - SCOPUS:85019578010

SN - 0092-8674

VL - 169

SP - 945-955.e10

JO - Cell

JF - Cell

IS - 5

ER -

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

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Keywords

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