Mouse Models of Human PWS/AS Imprinting Center Mutations

描述(申请人提供)：哺乳动物中的大多数基因都是表达的 同样来自母系和父系遗传的等位基因。然而，一些人 基因被印记，导致只有一个亲本有选择性地表达 等位基因。印记的一个结果是表达的等位基因发生突变 结果是尽管存在野生型，但没有基因产物， 而是沉默的等位基因。这是涉及相关但临床上的 不同的遗传性疾病Prader-Willi(PWS)和Angelman(AS)综合征 源于人类染色体基因组印记的相反模式 L5Q11-Q13。这个大约2Mb区域的印记由一个 双部印记中心(IC)，由AS-IC和PWS-IC组成。超过了 在过去的几年里，我们已经将鼠标作为一个模型系统来建立 研究15q11-q13印迹的规律，论证该地区 上游包括部分Snrpn基因作为PWS-IC。目标是 此续订应用程序的主要功能是利用鼠标剖析 这一地区的印记机制。我们的第一个具体目标是 研究PWS-IC在体细胞组织中的作用。第二个具体目标 是从功能上定义小鼠AS-IC并研究其在基因中的作用 监管。第三个具体目标是测试我们所建立的模型的预测 最近建议解释父母特定的地区模式 基因表达。最终的具体目标是利用我们新开发的 利用转基因技术鉴定最小顺式作用元件 Snrpn基因的印记。总之，这些实验将极大地 加深我们对IC如何调节印记基因的理解 在15q11-q13中表达。

DESCRIPTION (provided by applicant): Most genes in mammals are expressed equally from the maternally and paternally inherited alleles. However, some genes are imprinted, resulting in selective expression from only one parental allele. One consequence of imprinting is that mutation of the expressed allele results in the absence of a gene product despite the presence of a wild-type, but silent allele. This is the senario involved in the related but clinically distinct genetic disorders Prader-Willi (PWS) and Angelman (AS) syndromes which arise from opposite patterns of genomic imprinting of human chromosome l5q11-q13. Imprinting of this approximately 2 Mb region is regulated by a bipartate Imprinting Center (IC), composed of an AS-IC and a PWS-IC. Over the last several years, we have established the mouse as a model system for studying the regulation of 15q11-q13 imprinting, demonstrating that the region upstream and including a portion of the Snrpn gene serves as a PWS-IC. The goal of this renewal application is to take advantage of the mouse to dissect the mechanism of imprinting in this region. Our first specific aim is to investigate the role of the PWS-IC in somatic tissues. The second specific aim is to functionally define the murine AS-IC and investigate its role in gene regulation. The third specific aim is to test predictions of a model that we have recently proposed to explain the regional pattern of parental specific gene expression. The final specific aim is to make use of our newly developed transgenic assay to identify the minimal cis-acting elements responsible for the imprinting of the Snrpn gene. Together, these experiments will greatly increase our understanding of how the IC serves to regulate imprinted gene expression in 15q11-q13.