Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice
Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice
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DOI：
10.1006/nbdi.2001.0463
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发表时间：
2002-03-01
影响因子：
6.1
通讯作者：
Wagstaff, J
中科院分区：
文献类型：
--
作者：
Miura, K;Kishino, T;Wagstaff, J
Angelman综合征（AS）是由染色体15 q11-q13（包括UBE 3A基因突变）的多种遗传病因引起的，以运动功能障碍、智力低下和癫痫发作为特征。UBE 3A编码UBE 3A/E6-AP，一种泛素蛋白连接酶，并显示脑特异性印迹，脑表达主要来自母体等位基因。缺乏UBE 3A的功能性母体等位基因导致AS。为了了解母体Ube 3A突变与AS之间的因果关系，我们构建了Ube 3a靶向失活的小鼠模型。失活等位基因含有lacZ报告基因，用于分析脑特异性印迹。母体而非父系传递靶向等位基因导致海马和小脑神经元中的β-半乳糖苷酶活性。Ube 3a突变等位基因的母体遗传也会导致运动功能和空间学习测试中的表现受损，以及海马EEG记录异常。正如从UBE 3A介导的p53对HPV E6蛋白的不液化依赖性所预测的那样，我们的母体缺陷小鼠显示出正常的脑p53水平。(C)2002 Elsevier Science（美国）。
Angelman syndrome (AS), characterized by motor dysfunction, mental retardation, and seizures, is caused by several genetic etiologies involving chromosome 15q11-q13, including mutations of the UBE3A gene. UBE3A encodes UBE3A/E6-AP, a ubiquitin-protein ligase, and shows brain-specific imprinting, with brain expression predominantly from the maternal allelle. Lack of a functional maternal allele of UBE3A causes AS. In order to understand the causal relationship between maternal UBE3A mutations and AS, we have constructed a mouse model with targeted inactivation of Ube3a. The inactive allele contains a lacZ reporter gene for analysis of brain-specific imprinting. Maternal, but not paternal, transmission of the targeted allele leads to beta-galactosidase activity in hippocampal and cerebellar neurons. Maternal inheritance of the Ube3a mutant allele also causes impaired performance in tests of motor function and spatial learning, as well as abnormal hippocampal EEG recordings. As predicted from the dependence of UBE3A-mediated ubliquitination of p53 on HPV E6 protein, our maternal-deficient mice show normal brain p53 levels. (C) 2002 Elsevier Science (USA).