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在Mecp2突变小鼠中,Ube3a的表达没有改变。

Ube3a expression is not altered in Mecp2 mutant mice.

作者信息

Jordan Charandle, Francke Uta

机构信息

Department of Genetics, Stanford University School of Medicine, CA 94305-5323, USA.

出版信息

Hum Mol Genet. 2006 Jul 15;15(14):2210-5. doi: 10.1093/hmg/ddl146. Epub 2006 Jun 5.

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by cognitive regression, loss of purposeful hand movements and speech, stereotypies, ataxia, seizures, mental retardation and acquired microcephaly. Mutations in MECP2, encoding methyl-CpG-binding protein 2, are responsible for approximately 90% of classic RTT cases. RTT displays phenotypic overlap with Angelman syndrome, a disorder caused by loss of expression of the imprinted gene UBE3A. MeCP2 binds to methylated DNA and may alter the expression of imprinted genes, thereby suggesting a mechanistic link between the two disorders. Here, we tested the hypothesis that MeCP2 deficiency affects expression of Ube3a in mouse models of RTT. As Ube3a is only imprinted in brain, we evaluated Ube3a expression in brains of 15 different litters of neonatal or 8-week-old male Mecp2 mutant mice by real-time quantitative RT-PCR and western blot analysis. We found no significant differences between Mecp2(tm1.1Bird/Y) or Mecp2(tm1.1Jae/Y) mutants and their wild-type male siblings that served as negative controls. In positive control mice carrying a maternally inherited Ube3a deletion, Ube3a sense transcript and protein levels were drastically reduced. Our data contrast with two recent reports of substantially decreased Ube3a expression in brain tissues of MeCP2-deficient mice. We, therefore, challenge the conclusion that decreased UBE3A/Ube3a expression contributes to the pathophysiology of RTT.

摘要

瑞特综合征(RTT)是一种神经发育障碍,其特征为认知功能倒退、目的性手部动作和言语丧失、刻板动作、共济失调、癫痫发作、智力发育迟缓以及后天小头畸形。编码甲基化CpG结合蛋白2的MECP2基因突变导致了约90%的典型RTT病例。RTT与天使综合征存在表型重叠,天使综合征是一种由印记基因UBE3A表达缺失引起的疾病。MeCP2与甲基化DNA结合,并可能改变印记基因的表达,从而提示这两种疾病之间存在机制上的联系。在此,我们在RTT小鼠模型中检验了MeCP2缺陷会影响Ube3a表达这一假说。由于Ube3a仅在脑中印记,我们通过实时定量RT-PCR和蛋白质印迹分析评估了15窝不同的新生或8周龄雄性Mecp2突变小鼠脑内的Ube3a表达。我们发现Mecp2(tm1.1Bird/Y)或Mecp2(tm1.1Jae/Y)突变体与其作为阴性对照的野生型雄性同胞之间没有显著差异。在携带母系遗传的Ube3a缺失的阳性对照小鼠中,Ube3a正义转录本和蛋白质水平大幅降低。我们的数据与最近两篇关于MeCP2缺陷小鼠脑组织中Ube3a表达大幅降低的报道形成对比。因此,我们对UBE3A/Ube3a表达降低导致RTT病理生理学改变这一结论提出质疑。

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