A Bama miniature pig model of monoallelic TSC1 mutation for human tuberous sclerosis complex
A Bama miniature pig model of monoallelic TSC1 mutation for human tuberous sclerosis complex
复制标题
巴马小型猪人结节性硬化症单等位基因 TSC1 突变模型
DOI：
10.1016/j.jgg.2020.11.005
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发表时间：
2020-12-20
影响因子：
5.9
通讯作者：
Dai, Yifan
中科院分区：
文献类型：
--
作者：
Li, Xiaoxue;Hu, Tingdong;Dai, Yifan
结节性硬化症（TSC）是一种显性遗传性神经皮肤综合征，以多器官错构瘤为特征。尽管已经产生了带有 TSC1 或 TSC2 基因种系突变的啮齿动物模型，但由于小鼠和人类之间存在显着差异，它们不会出现与 TSC 患者中所见的致病病变相匹配的病变，这凸显了对改进的 TSC 大型动物模型的需求。在这里，我们利用 CRISPR/Cas9 系统和体细胞核移植 (SCNT) 技术成功培育出单等位基因 TSC1 修饰的巴马小型猪。仔猪中磷酸化靶核糖体蛋白 S6 的表达显着增强，表明 TSC1 等位基因的破坏激活了雷帕霉素 (mTOR) 信号通路的机制靶点。值得注意的是，与之前报道的小鼠 TSC 模型不同，TSC1(+/-) 巴马小型猪出现了心脏横纹肌瘤和室管膜下结节，与 TSC 患者的主要临床特征相似。这些TSC1(+/-)巴马小型猪可以作为有价值的大型动物模型，用于进一步阐明TSC的发病机制和制定TSC疾病的治疗策略。版权所有(C)2021，中国科学院遗传与发育生物学研究所，中国遗传学会。由爱思唯尔有限公司和科学出版社出版。版权所有。
Tuberous sclerosis complex (TSC) is a dominant genetic neurocutaneous syndrome characterized by multiple organ hamartomas. Although rodent models bearing a germline mutation in either TSC1 or TSC2 gene have been generated, they do not develop pathogenic lesions matching those seen in patients with TSC because of the significant differences between mice and humans, highlighting the need for an improved large animal model of TSC. Here, we successfully generate monoallelic TSC1-modified Bama miniature pigs using the CRISPR/Cas9 system along with somatic cell nuclear transfer (SCNT) technology. The expression of phosphorylated target ribosomal protein S6 is significantly enhanced in the piglets, indicating that disruption of a TSC1 allele activate the mechanistic target of rapamycin (mTOR) signaling pathway. Notably, differing from the mouse TSC models reported previously, the TSC1(+/-) Bama miniature pig developed cardiac rhabdomyoma and subependymal nodules, resembling the major clinical features that occur in patients with TSC. These TSC1(+/-) Bama miniature pigs could serve as valuable large animal models for further elucidation of the pathogenesis of TSC and the development of therapeutic strategies for TSC disease. Copyright (C) 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.