Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of Tuberous Sclerosis Complex
Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of Tuberous Sclerosis Complex
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在结节性硬化症小鼠模型中，Tsc2 基因失活导致比 Tsc1 失活更严重的癫痫表型
DOI：
10.1093/hmg/ddq491
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发表时间：
2011-02-01
影响因子：
3.5
通讯作者：
Wong, Michael
中科院分区：
文献类型：
--
作者：
Zeng, Ling-Hui;Rensing, Nicholas R.;Wong, Michael
多发性硬化症（TSC）是一种常染色体显性遗传的多系统疾病，通常涉及严重的神经系统症状，如癫痫、认知缺陷和自闭症。已鉴定出两种基因，TSC 1和TSC 2，分别编码蛋白质hamartin和tuberin，引起TSC。尽管TSC 1和TSC 2突变产生的临床表型存在大量重叠，但越来越多的证据表明TSC 2突变比TSC 1突变导致更严重的神经系统表现。在这项研究中，一种新的小鼠模型，涉及条件性失活的Tsc2基因的胶质细胞酸性蛋白（GFAP）阳性细胞（Tsc2（GFAP 1）CKO小鼠）的神经系统表型的特点，并与以前产生的Tsc1（GFAP 1）CKO小鼠进行比较。与Tsc 1（GFAP 1）CKO小鼠相似，Tsc 2（GFAP 1）CKO小鼠表现出癫痫、过早死亡、进行性大头畸形、弥漫性胶质细胞增生、海马锥体细胞分散和星形胶质细胞谷氨酸转运蛋白表达降低。然而，与Tsc1（GFAP 1）CKO小鼠相比，Tsc2（GFAP 1）CKO小鼠具有更早的发作和更高的癫痫发作频率，以及更严重的组织学异常。Tsc 1（GFAP 1）CKO和Tsc 2（GFAP 1）CKO小鼠之间的差异与Tsc 2（GFAP 1）CKO小鼠中较高水平的哺乳动物雷帕霉素靶蛋白（mTOR）激活相关，并被mTOR抑制剂雷帕霉素逆转。这些发现在小鼠模型中提供了新的证据，即Tsc 2突变本质上导致比Tsc 1突变更严重的神经系统表型，并表明表型的差异可能与Tsc 1和Tsc 2失活导致异常mTOR激活的程度有关。
Tuberous Sclerosis Complex (TSC) is an autosomal dominant, multi-system disorder, typically involving severe neurological symptoms, such as epilepsy, cognitive deficits and autism. Two genes, TSC1 and TSC2, encoding the proteins hamartin and tuberin, respectively, have been identified as causing TSC. Although there is a substantial overlap in the clinical phenotype produced by TSC1 and TSC2 mutations, accumulating evidence indicates that TSC2 mutations cause more severe neurological manifestations than TSC1 mutations. In this study, the neurological phenotype of a novel mouse model involving conditional inactivation of the Tsc2 gene in glial-fibrillary acidic protein (GFAP)-positive cells (Tsc2(GFAP1)CKO mice) was characterized and compared with previously generated Tsc1(GFAP1)CKO mice. Similar to Tsc1(GFAP1)CKO mice, Tsc2(GFAP1)CKO mice exhibited epilepsy, premature death, progressive megencephaly, diffuse glial proliferation, dispersion of hippocampal pyramidal cells and decreased astrocyte glutamate transporter expression. However, Tsc2(GFAP1)CKO mice had an earlier onset and higher frequency of seizures, as well as significantly more severe histological abnormalities, compared with Tsc1(GFAP1)CKO mice. The differences between Tsc1(GFAP1)CKO and Tsc2(GFAP1)CKO mice were correlated with higher levels of mammalian target of rapamycin (mTOR) activation in Tsc2(GFAP1)CKO mice and were reversed by the mTOR inhibitor, rapamycin. These findings provide novel evidence in mouse models that Tsc2 mutations intrinsically cause a more severe neurological phenotype than Tsc1 mutations and suggest that the difference in phenotype may be related to the degree to which Tsc1 and Tsc2 inactivation causes abnormal mTOR activation.