GENOMIC IMPRINTING OF HUMAN CHROMOSOME 15Q

描述（改编自研究者摘要）：Angelman综合征（AS） 是一种以严重智力迟钝为特征的遗传性疾病， “木偶样”共济失调步态，手臂运动不稳，多动， 癫痫发作 AS是由于缺乏正常的母亲贡献， 染色体15 q11 q13，一个受基因组印记影响的区域。 那里 是几种分子类型的AS，包括缺失、单亲二体性 和印记突变。 此外，突变现已确定， AS候选基因UBE 3A。 这些发现表明，不仅 由印迹UBE 3A基因的缺失或突变引起，但也 是因为印记过程的失调 更好地了解 印记的功能以及异常印记如何导致 等位基因特异性转录和DNA甲基化对于阐明 AS和其他印迹遗传病的分子发病机制。 本报告提出了与这一问题有关的三个主要调查领域 这里. 第一个是研究UBE 3A的组织特异性印迹， 表征其启动子并研究其在不同组织中的活性 其中UBE 3A要么被压印要么不被压印。 UBE 3A基因组区域也将 搜索等位基因特异性甲基化和核酸酶的位点 超敏反应 拟议研究的第二个主要领域涉及 GABRA 5的5 '-末端的重复的表征， 转座到15 q11 q13区域近端的一个位点上， PWS和AS。 重复的区域显示等位基因甲基化，并且是一个 最近的进化事件 对该基因座的进一步研究可能会提供一个独特的 有机会深入了解等位基因甲基化是如何 确立了习 最后，我们将继续研究 近端15 q的同源联合及其在细胞凋亡中的潜在作用 在这个区域的印记的调节。

DESCRIPTION (Adapted from investigator's abstract): Angelman syndrome (AS) is a genetic disease characterized by severe mental retardation, "puppet-like" ataxic gait with jerky arm movements, hyperactivity and seizures. AS is caused by the absence of a normal maternal contribution to chromosome 15q11q13, a region that is subject to genomic imprinting. There are several molecular classes of AS including deletion, uniparental disomy and imprinting mutation. In addition, mutations have now been identified in a candidate AS gene, UBE3A. These findings indicate that AS not only results from the deletion or mutation of the imprinted UBE3A gene but also from a disregulation of the imprinting process. A better understanding of the function of imprinting and of how abnormal imprinting leads to loss of allele-specific transcription and DNA methylation is crucial to elucidating the molecular pathogenesis of AS and other imprinted genetic diseases. Three major areas of investigation related to this question are proposed here. The first is to study the tissue-specific imprinting of UBE3A by characterizing its promoter and studying its activity in different tissues where UBE3A is either imprinted or not. The UBE3A genomic region will also be searched for sites of allele-specific methylation and nuclease hypersensitivity. The second major area of proposed research involves the characterization of a duplication of the 5'-end of GABRA5 that has transposed to a locus proximal to the 15q11q13 region commonly deleted in PWS and AS. The duplicated region displays allelic methylation and is a recent evolutionary event. Further study of this locus may offer a unique opportunity to gain some insight into how allelic methylation is established. Finally, we will continue to investigate the mechanism of the homologous association of proximal 15q and its potential role in the regulation of imprinting in this region.