GENETIC COMPLEMENTATION OF A MOUSE MODEL FOR PWS

描述：（改编自研究者摘要）这项新提案概述了 Prader-Willi小鼠模型的一系列互补实验 综合征，这是以前由研究者构建的。述临床 不同的遗传性疾病Prader-Willi（PWS）和Angelman（AS）综合征出现 来自人类染色体15q11-q13的基因组印记的相反模式。PWS 结果从父亲的基因表达的损失，和AS的结果从损失 母体基因表达这一建议的依据是， 有一类人AS患者，其在单个 由于致病基因，尚未确定类似的PWS患者类别。这 表明PWS是一种连续基因综合征，由缺乏 两个或多个印记基因的表达。单个敲除突变 在所确定的四个基因中的每一个中创建，因为PWS的候选人没有 在小鼠中发现了一种表型。 研究人员最近创建了一个涉及全局的缺失突变， 调节元件，称为印记中心，并产生了小鼠模型 对于PWS。在该模型中，所有四个PWS候选基因都被沉默。的 第一个具体目标是利用这种小鼠模型来测试 两个或两个以上的基因负责PWS的假说。该战略将 为了确定候选基因的哪种组合在表达为 转基因能够补充PWS小鼠模型。第二个具体目标 是将这种互补分析扩展到研究 通过使用组织限制性表达的 互补转基因。

DESCRIPTION: (Adapted from investigator's abstract) This new proposal outlines a series of complementation experiments of a mouse model of Prader-Willi syndrome, which was previously constructed by the investigator. The clinically distinct genetic disorders Prader-Willi (PWS) and Angelman (AS) syndromes arise from opposite patterns of genomic imprinting of human chromosome 15q11-q13. PWS results from loss of paternal gene expression, and AS results from a loss of maternal gene expression. This proposal is based on the finding that while there is a class of human AS patients, which have point mutations in a single causative gene, a similar class of PWS patients has not been identified. This suggests that PWS is a contiguous gene syndrome, caused by the lack of expression of two or more imprinted genes. Individual knock-out mutations created in each of the four genes identified, as candidates for PWS have not revealed a phenotype in mice. The investigator has recently created a deletion mutation involving a global regulatory element, called the Imprinting Center, and produced a mouse model for PWS. In this model, all four of the PWS candidate genes are silenced. The first specific aim is to take advantage of this mouse model to test the hypothesis that two or more genes are responsible for PWS. The strategy will be to determine which combination of the candidate genes when expressed as transgenes are able to complement the PWS mouse model. The second specific aim is to extend this complementation assay to investigate the anatomical sites of the various PWS clinical features by using tissue-restricted expression of the complementing transgene(s).