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: 6698580
• 负责人: JAMES L RESNICK
• 金额: $ 24.9万
• 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/6698580
• 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（由申请人提供）：哺乳动物中的大多数基因都有表达 同样来自母系和父系遗传的等位基因。然而，一些 基因被印记，导致仅来自一个亲本的选择性表达 等位基因。印记的后果之一是表达的等位基因发生突变 尽管存在野生型，但导致基因产物缺失， 但沉默等位基因。这是涉及相关但临床上的情况 不同的遗传性疾病普瑞德-威利 (PWS) 和天使 (AS) 综合征 由人类染色体基因组印记的相反模式产生 l5q11-q13。这个大约 2 Mb 区域的印记由 双部分印记中心（IC），由 AS-IC 和 PWS-IC 组成。超过 过去几年，我们建立了鼠标作为模型系统 研究 15q11-q13 印记的调控，证明该区域 上游并包含 Snrpn 基因的一部分作为 PWS-IC。目标 这个续订应用程序的主要功能是利用鼠标来剖析 该区域的印记机制。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 的目的是从功能上定义小鼠 AS-IC 并研究其在基因中的作用 规定。第三个具体目标是测试我们模型的预测 最近提出解释父母特定的区域模式 基因表达。最终的具体目标是利用我们新开发的 转基因测定来鉴定负责的最小顺式作用元件 Snrpn 基因的印记。总之，这些实验将极大地 增加我们对 IC 如何调节印记基因的理解 15q11-q13 中的表达。