GENETIC COMPLEMENTATION OF A MOUSE MODEL FOR PWS

描述：(改编自调查人员摘要)这份新提案概述了 Prader-Willi小鼠模型的一系列补充实验 综合症，这是由研究人员先前构建的。临床上的 出现不同的遗传性疾病Prader-Willi(PWS)和Angelman(AS)综合征 来自人类染色体15q11-q13相反的基因组印记模式。PWS 由于父亲基因表达的缺失，以及AS基因表达的缺失 母体基因表达。这项建议是基于这样一个发现：虽然 有一类人类AS患者，在单个基因中有点突变 致病基因，一类类似的PWS患者尚未被鉴定。这 提示PWS是一种邻近的基因综合征，由缺乏 两个或多个印记基因的表达。个体基因敲除突变 在确定的四个基因中每一个都创造了，作为PWS的候选基因还没有 在小鼠身上发现了一种表型。 研究人员最近创造了一种缺失突变，涉及一种全球 被称为印记中心的调控元件，并生产了一个老鼠模型 对于PWS。在这个模型中，所有四个PWS候选基因都是沉默的。这个 第一个具体目标是利用这个鼠标模型来测试 假设有两个或更多的基因对PWS负责。战略将是 以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 是将这一互补分析扩展到研究 应用组织限制性表达技术研究PWS的不同临床特征 补充转基因(S)。

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).