UNDERSTANDING OUTFLOW TRACT DEFECTS IN DIGEORGE SYNDROME--CHROMOSOME ENGINEERING

了解迪乔治综合征的流出道缺陷——染色体工程

• 批准号: 6594622
• 负责人: ANTONIO BALDINI
• 金额: $ 17.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594622
• 关键词: DiGeorge's syndrome; chromosome aberrations; congenital heart disorder; gene deletion mutation; gene targeting; laboratory mouse

The hemizygous deletion of a chromosomal region of human 22q11 is the genetic basis for several developmental defects with variable clinical severity. The clinical presentations may fit the diagnostic criteria for DiGeorge syndrome (DGS), Velocardiofacial syndrome (VCFS) or be very mild or complex. Approximately 80% of patients with a 22q11 deletion (de122q11) presents with a congenital heart defects, mostly of conotruncal origin and affecting the outflow tract of the heart. Heart defects represent the most dramatic clinical findings and are responsible for virtually all the early deaths in these patients. As the 22q11 deletion is one of the most frequent chromosomal deletions associated with an anomalous phenotype known in humans, this genetic lesions represents an important cause of heart defects. Furthermore, we have shown that for certain specific defects, such as interrupted aortic arch type B, the deletion is found in 50% of the cases, hence representing a major genetic cause for this anomaly. A 'critical region' the deletion of which is sufficient to produce the de122q11 phenotype has been delineated. As of today, at least 9 genes have been identified in this 300-400 kb interval. However, it is still unknown whether or not any of these genes is etiologically important for the phenotype or whether this is a single or multiple gene defect. We propose a novel and powerful approach for the modeling of this important deletion syndrome. We will use chromosome engineering to generate mouse deletions which simulate the human deletion. Deletions will be generated using the Cre-loxP strategy in embryonic stem (ES) cells. Mice carrying the deficiencies will be obtained to test the phenotypic effects of the deficiencies. Transgenic rescue experiments will be performed to complement in vivo the deficiencies and identify a genomic segment sufficient to rescue the phenotype. With these approaches we will be able to dissect genetically the mechanisms which lead to the developmental heart defects typical of the de122q11 phenotype.

人类22q11的染色体区域的半合子缺失是 具有可变临床的几种发育缺陷的遗传基础 严重程度。临床演示可能符合诊断标准 Digeorge综合征（DGS），速食综合征（VCF）或非常温和 或复杂。大约80％的22q11缺失患者（DE122Q11） 呈现先天性心脏缺陷，主要是conruncal的起源和 影响心脏的流出道。心脏缺陷最多 戏剧性的临床发现，几乎是所有早期的 这些患者死亡。因为22q11删除是最多的 与异常表型相关的频繁染色体缺失 在人类中，这种遗传病变代表了 心脏缺陷。此外，我们已经证明了某些特定 缺陷，例如中断主动脉弓类型B，删除在 50％的病例，因此代表了这一点的主要遗传原因 异常。 “关键区域”的删除足以 产生DE122Q11表型已被描述。截至今天，至少 在300-400 kb的间隔中已经确定了9个基因。但是，是 这些基因中的任何一个在病因学上是否都不清楚 对于表型，还是单个基因缺陷。 我们为建模提出了一种新颖而有力的方法 重要的缺失综合征。我们将使用染色体工程 产生鼠标缺失，以模拟人类缺失。删除会 使用胚胎茎（ES）细胞中的CRE-LoxP策略生成。 将获得携带缺陷的小鼠测试表型 缺陷的影响。转基因救援实验将是 进行的以补充体内缺陷并识别基因组 足以营救表型的段。通过这些方法，我们将 能够从遗传上剖析导致的机制 DE122Q11表型的典型发育心脏缺陷。