Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing
Abstract Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deamina...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2020-07-01
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| Series: | Protein & Cell |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s13238-020-00740-8 |
| _version_ | 1827847838107697152 |
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| author | Fang Wang Weiqi Zhang Qiaoyan Yang Yu Kang Yanling Fan Jingkuan Wei Zunpeng Liu Shaoxing Dai Hao Li Zifan Li Lizhu Xu Chu Chu Jing Qu Chenyang Si Weizhi Ji Guang-Hui Liu Chengzu Long Yuyu Niu |
| author_facet | Fang Wang Weiqi Zhang Qiaoyan Yang Yu Kang Yanling Fan Jingkuan Wei Zunpeng Liu Shaoxing Dai Hao Li Zifan Li Lizhu Xu Chu Chu Jing Qu Chenyang Si Weizhi Ji Guang-Hui Liu Chengzu Long Yuyu Niu |
| author_sort | Fang Wang |
| collection | DOAJ |
| description | Abstract Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates. |
| first_indexed | 2024-03-12T09:37:11Z |
| format | Article |
| id | doaj.art-7a8e00cae52146e1a0fbcd2edf18bf19 |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T09:37:11Z |
| publishDate | 2020-07-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-7a8e00cae52146e1a0fbcd2edf18bf192023-09-02T13:34:10ZengOxford University PressProtein & Cell1674-800X1674-80182020-07-01111180982410.1007/s13238-020-00740-8Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editingFang Wang0Weiqi Zhang1Qiaoyan Yang2Yu Kang3Yanling Fan4Jingkuan Wei5Zunpeng Liu6Shaoxing Dai7Hao Li8Zifan Li9Lizhu Xu10Chu Chu11Jing Qu12Chenyang Si13Weizhi Ji14Guang-Hui Liu15Chengzu Long16Yuyu Niu17Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyInstitute for Stem Cell and Regeneration, Chinese Academy of ScienceThe Leon H Charney Division of Cardiology, New York University School of MedicineYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyUniversity of Chinese Academy of SciencesYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyInstitute for Stem Cell and Regeneration, Chinese Academy of ScienceYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyInstitute for Stem Cell and Regeneration, Chinese Academy of ScienceThe Leon H Charney Division of Cardiology, New York University School of MedicineYunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyAbstract Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.https://doi.org/10.1007/s13238-020-00740-8base editingnon-human primateHGPS |
| spellingShingle | Fang Wang Weiqi Zhang Qiaoyan Yang Yu Kang Yanling Fan Jingkuan Wei Zunpeng Liu Shaoxing Dai Hao Li Zifan Li Lizhu Xu Chu Chu Jing Qu Chenyang Si Weizhi Ji Guang-Hui Liu Chengzu Long Yuyu Niu Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing Protein & Cell base editing non-human primate HGPS |
| title | Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing |
| title_full | Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing |
| title_fullStr | Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing |
| title_full_unstemmed | Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing |
| title_short | Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing |
| title_sort | generation of a hutchinson gilford progeria syndrome monkey model by base editing |
| topic | base editing non-human primate HGPS |
| url | https://doi.org/10.1007/s13238-020-00740-8 |
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