GENES FROM DEL22Q11 INVOLVED IN HEART DEVELOPMENT

描述（改编自研究者摘要）：这是修订后的RO 1 申请为期四年的支持，以确定小鼠中负责 与人类22 qdel综合征相关的先天性心脏病。主要研究者有 最近证明，约1 Mb Cre介导的缺失， 在Ufd 1 l和Es 2之间延伸导致第4主动脉弓异常 这些衍生物与在人类中发现的具有常见22 q缺失的那些非常相似。 相同区域的重复-作为相互重组恢复 串联lox位点之间的产物-防止心脏异常， 重复/缺陷杂合子，这表明， 基因或基因内的缺失是负责的特征性心脏 缺损自上次以来获得的初步数据， 提交的意见书表明，第四个足弓异常所需的序列 位于一个150 kb的“关键区域”内， 更大的区域将足以挽救该异常。的序列 整个区域已经确定。在本申请中，PI 建议测试互补3 BAC或PAC克隆，跨越该地区 (Aim 1）。补充BAC中的单个候选人将由以下人员进行评估： 基因靶向（目标2），并将研究正确候选物的功能 进一步通过分析纯合突变表型，可能在上下文中， 一个条件等位基因。

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.