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: 6593873
• 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/6593873
• 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22 q11染色体区域的半合子缺失是 几种发育缺陷的遗传基础， 严重性。临床表现可能符合以下诊断标准： DiGeorge综合征（DGS）、速度心面综合征（VCFS）或非常轻微 或复杂。大约80%的22 q11缺失患者（de 122 q11） 存在先天性心脏缺陷，主要是圆锥动脉干起源， 影响心脏流出道心脏缺陷是最常见的 戏剧性的临床发现，并负责几乎所有的早期 这些病人的死亡。由于22 q11缺失是最常见的 与异常表型相关的频繁染色体缺失 在人类中已知，这种遗传病变是导致 心脏缺陷此外，我们还表明，对于某些特定的 缺损，如主动脉弓中断B型，缺失见于 50%的病例，因此代表了其主要遗传原因 异常一个“关键区域”，其删除足以 产生de 122 q11表型。至少从今天开始 在这300-400 kb的区间内已经鉴定了9个基因。但据 这些基因中是否有重要的致病基因仍不清楚 或者是单基因缺陷还是多基因缺陷。 我们提出了一种新的和强大的方法来建模这一点 重要缺失综合征我们将利用染色体工程 产生模拟人缺失的小鼠缺失。删除将 使用Cre-loxP策略在胚胎干（ES）细胞中产生。 将获得携带缺陷的小鼠以测试表型 缺陷的影响。转基因拯救实验将是 进行体内补充缺陷并鉴定基因组 足以拯救表型的片段。通过这些方法，我们将 能够从基因上剖析导致 de 122 q11表型典型的发育性心脏缺陷。