GENETIC BASIS OF CONOTRUNCAL MALFORMATIONS

圆锥干心脏缺陷约占先天性心脏缺陷的17%，尽管在识别调节心肌分化和心脏循环的基因方面取得了令人印象深刻的进展，但调节流出道个体发育的机制仍然不清楚。研究人员将重点放在染色体22q11缺失区域内的基因的作用上，以此作为理解流出道病理的一种方法。现在很明显，这不是唯一的原因，也不总是足以造成异常。这有力地表明了基因修饰物的存在。在费城儿童医院儿童心血管疾病SCOR更新中提出的五个项目和三个核心的目标是，利用现已建立的合作伙伴联盟，在22q11内继续评估基因，并扩大重点，以确定和表征可能在正常流出道形态发生中发挥作用的新的分子途径。临床项目1将寻求一种策略，以确定22q11缺失患者的心脏表型修饰因素以及非缺失患者导致流出道缺陷的基因。项目2将采用候选基因方法来确定Jagged1和其他Notch信号配体突变在圆锥干缺陷中的作用。项目3将继续鉴定人类22q11基因的小鼠同源物，并独立鉴定在心脏圆锥干区唯一表达的基因。项目4将描述一种新的内皮特异性转录因子NFATc在半月瓣缺陷个体发育中的作用，项目5将探索Pax3调控元件在心脏神经脊形态发生行为中的作用。临床核心将继续是SCOR的重点。该中心已经收集了400多名圆锥干心脏缺陷患者的样本，它将扩大这个数据库的范围，包括家庭成员和患有相关心血管缺陷的患者。分子和细胞遗传学核心将在基因的染色体图谱方面提供额外的服务，基因表达核心将表征它们的发育表达。通过儿科心脏病专家、分子生物学家、发育生物学家和遗传学家的共同努力，利用世界上最大的儿科心脏病中心之一的资源，研究人员将能够确定与圆锥干发育有关的关键基因的功能，从而开始了解一组影响世界各地儿童的最常见先天性心脏病的分子病因学。

(Adapted from the Applicant's Abstract) Conotruncal cardiac defects account for approximately 17 percent of congenital heart defects and, while impressive progress has been made in identifying genes that regulate myocardial differentiation and looping of the heart, mechanisms regulating outflow tract ontogeny remain obscure. The investigators have focused on the role of genes within the deleted region of chromosome 22q11 as an approach to understanding outflow tract pathology. It is now evident that this is not the sole cause nor always sufficient to cause an abnormality. This strongly suggests the existence of genetic modifiers. Capitalizing on a now well established consortium of collaborators, the goal of the five projects and three cores proposed in this renewal of the SCOR in Pediatric Cardiovascular Diseases at the Children's Hospital of Philadelphia is to continue to evaluate genes within 22q11 and expand the focus to identify and characterize new molecular pathways which might play a role in normal outflow tract morphogenesis Project 1, the clinical project, will pursue a strategy to identify factors which act as modifiers of the cardiac phenotype in 22q11 deleted patients as well as identify genes that cause outflow tract defects in non-deleted patients. Project 2 will pursue a candidate gene approach in defining the role of mutations in Jagged1 and other Notch signaling ligands as causative agents in conotruncal defects. Project 3 will continue to characterize the mouse homologues of human 22q11 genes as well as to independently identify genes uniquely expressed in the conotruncal region of the heart. Project 4 will delineate the role of NFATc, a novel endothelial specific transcription factor, in the ontogeny of semilunar valve defects, and Project 5 will explore the role of Pax3 regulatory elements in control of the morphogenetic behavior of the cardiac neural crest. The Clinical Core will continue to be the focal point of the SCOR. This Core has collected samples from over 400 patients with conotruncal cardiac defects, it will expand this data base to include family members and patients with related cardiovascular defects. The Molecular and Cytogenetics Core will be providing additional services in the chromosomal mapping of genes and the Gene Expression Core will characterize their developmental expression. Through this combined effort of pediatric cardiologists, molecular biologists, developmental biologists, and geneticists, utilizing the resources of one of the world's largest pediatric cardiology centers, the investigators will be able to determine the function of critical genes involved in conotruncal development and thus begin to comprehend the molecular etiology of a set of the most common congenital heart defects affecting children throughout the world.