GENES FROM DEL22Q11 INVOLVED IN HEART DEVELOPMENT

描述(改编自调查人员摘要)：这是修改后的RO1 申请四年的支持，以确定小鼠的基因负责 与人类22qdel综合征相关的先天性心脏病。少年派有 最近证明，大约1Mb的Cre介导的缺失 Ufd1和ES2之间的延伸导致第四主动脉弓异常 与人类中常见的22q缺失的衍生品非常相似。 相同区域的复制--恢复为互惠重组 在串联lox位置之间的产品-预防心脏异常 重复/缺失杂合子，表明单倍性不全 基因或基因内的缺失是导致特征性心脏疾病的原因 叛逃。自上一次会议以来获得的初步数据，但有其他不足之处 意见书表明，第四个拱门异常所需的序列 位于150 kb的“临界区”内，与之互补的是 更大的区域将足以挽救这种异常。按顺序排列 整个地区已经确定了。在当前应用程序中，PI 建议测试跨越该地区的3个BAC或PAC克隆的互补性 (目标1)。补充性BAC中的个人候选人将通过 基因打靶(目标2)，以及正确候选人的功能将被研究 进一步通过分析纯合子突变表型，可能在上下文中 条件等位基因。

DESCRIPTION (Adapted from investigator's abstract): This is a revised RO1 application for four years of support to identify genes in mice responsible for congenital heart disease associated with the human 22qdel syndrome. The PI has recently demonstrated that an approximately 1 Mb Cre-mediated deletion that extends between Ufd1l and Es2 causes abnormalities of 4th aortic arch derivatives very similar to those found in humans with the common 22q deletion. A duplication of the same region-recovered as a reciprocal recombination product between tandem lox sites-prevents cardiac abnormalities in duplication/deficiency heterozygotes, suggesting that haploinsufficiency for a gene or genes within the deletion is responsible for the characteristic cardiac defect. Preliminary data obtained with additional deficiencies since the last submission suggests that the sequence necessary for the 4th arch abnormality lies within a 150 kb "critical region" and that complementation with a slightly larger region would be sufficient to rescue that abnormality. The sequence of the entire region has been determined. In the current application, the PI proposes to test for complementation 3 BAC or PAC clones that span the region (Aim 1). Individual candidates within a complementing BAC will be evaluated by gene targeting (Aim 2), and function of correct candidate will be investigated further by analyzing the homozygous mutant phenotype, possibly in the context of a conditional allele.