Mouse Models of Human PWS/AS Imprinting Center Mutations

人类 PWS/AS 印记中心突变的小鼠模型

• 批准号: 6846248
• 负责人: JAMES L RESNICK
• 金额: $ 24.85万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846248
• 关键词: Prader Willi syndrome; alleles; animal genetic material tag; disease /disorder model; gene deletion mutation; gene expression; genetic models; genetic regulatory element; genetically modified animals; genomic imprinting; happy puppet syndrome; laboratory mouse; methylation; model design /development; open reading frames; radionuclides; restriction fragment length polymorphism; tissue /cell culture

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.

描述（申请人提供）：哺乳动物中的大多数基因都表达 来自父系和母系遗传的等位基因。但也有 基因是印记的，导致只有一个亲本的选择性表达 等位基因印记的一个后果是， 导致尽管存在野生型但基因产物不存在， 但是沉默的等位基因。这是塞纳里奥参与相关的，但临床上 不同的遗传性疾病Prader-Willi（PWS）和Angelman（AS）综合征， 是由人类染色体的基因组印记的相反模式引起的 l5q11-q13。这一约2 Mb区域的印记由一个 由AS-IC和PWS-IC组成的两部分印记中心（IC）。来 在过去的几年里，我们已经建立了小鼠作为模型系统， 研究了15 q11-q13印迹的调控，表明该区域 上游并包括Snrpn基因的一部分作为PWS-IC。目标 这个更新应用程序是利用鼠标解剖 在这个区域的印记机制。我们的首要目标是 研究PWS-IC在体细胞组织中的作用。第二个具体目标 目的是对小鼠AS-IC进行功能性定义，并研究其在基因表达中的作用。 调控第三个具体目标是测试一个我们 最近提出了解释父母特定的区域模式， 基因表达。最后的具体目标是利用我们新开发的 转基因测定，以确定最小顺式作用元件负责 Snrpn基因的印记。这些实验将大大 增加我们对IC如何调节印记基因的理解 表达于15 q11-q13。