THE GENETIC ETIOLOGY OF HYPOPLASTIC LEFT HEART SYNDROME

左心发育不全综合征的遗传病因

• 批准号: 6039479
• 负责人: PETER N BOWERS
• 金额: $ 13.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-11 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6039479
• 关键词: artificial chromosomes; chromosome translocation; clinical research; congenital heart disorder; disease /disorder etiology; family genetics; fluorescent in situ hybridization; genetic mapping; genetic screening; human genetic material tag; human subject; single strand conformation polymorphism

Hypoplastic left heart syndrome (HLHS) is one of the most lethal forms of congenital cardiovascular malformation. Genetic epidemiological studies have demonstrated an increased prevalence of left heart obstructive disease in first degree relatives of patients with HLHS, suggesting a genetic etiology. HLHS is the severe, neonatal presentation of the spectrum of left heart obstructive diseases, which includes first trimester spontaneous abortion, HLHS, aortic and mitral stenosis, coarctation and bicuspid aortic valve. With 2 percent of the general population having a bicuspid aortic valve, these lesions are extremely common. By investigating a more severe phenotype such as HLHS, we may gain insight into the pathogenesis of the more common forms of left heart obstructive disease such as first trimester spontaneous abortions and bicuspid aortic valve. Jacobsen syndrome (characterized by translocation or terminal deletion of 11q23.3) is frequently associated with left heart obstructive disease and supports a gene locus for left heart obstruction at 11q23.3. We have a fibroblast cell line containing a de novo balanced translocation t(10; 11) (q24.3; q23.3) from a non-syndromic female infant with HLHS. This translocation is likely to disrupt a gene(s) at 11q23.3 that causes HLHS. We have physically mapped the breakpoint by fluorescence in situ hybridization to a single 1.5 Mb YAC clone. Using markers from the spanning YAC, we identified proximal and distal BACs by FISH. We describe both physical mapping and gene based approaches to identifying the disrupted 11q23.3 gene. Mutational screening of the 11q23.3 gene will utilize single- stranded conformational polymorphism analysis. With the 11q23.3 gene, clinical correlation studies using the cardiovascular phenotype and these genetic findings may establish that left heart obstruction shares a common pathogenesis. My career goals are to investigate the cause of HLHS and congenital cardiovascular malformations. The K08 will provide the necessary training in molecular genetics to accomplish these goals. Dr. Lifton is a recognized leader in cardiovascular genetics and his. mentorship is a vital component to my career development. The Departments of Pediatrics and Genetics at Yale combined with the extensive resources of the Lifton laboratory provide an ideal environment for acquiring the investigative skills needed to launch my research career. This award provides all of the essential components to develop my career and will maximize my academic potential.

左心脏综合征（HLHS）是先天性心血管畸形的最致命形式之一。 遗传流行病学研究表明，HLHS患者的一级亲属左心脏阻塞性疾病的患病率增加，这表明遗传病因学。 HLHS是左心阻塞性疾病光谱的严重，新生儿的表现，其中包括头三个月自发流产，HLHS，主动脉狭窄和二尖瓣狭窄，缩回和双质主动脉瓣。 由于有2％的一般人群具有双质主动脉瓣，因此这些病变非常普遍。 通过研究更严重的表型（例如HLHS），我们可以深入了解左心阻塞性疾病的更常见形式的发病机理，例如第一三个月自发流产和双刺主动脉瓣。雅各布森综合征（以易位或末端缺失为11q23.3）经常与左心梗阻性疾病有关，并支持11 Q23.3左心阻塞的基因基因座。 我们有一条成纤维细胞系，该细胞系包含从NLHS的非综合雌性婴儿中的从头平衡的易位T（10; 11）（Q24.3; Q23.3）。 这种易位可能会破坏导致HLHS的11q23.3的基因。 我们已经通过原位杂交到单个1.5 MB YAC克隆来物理地映射了断点。使用跨越YAC的标记，我们通过鱼类发现了近端和远端BAC。 我们描述了基于物理映射和基因的方法来识别破坏的11q23.3基因。 11q23.3基因的突变筛选将利用单链构象多态性分析。 借助11q23.3基因，使用心血管表型和这些遗传发现的临床相关研究可能确定左心阻塞具有常见的发病机理。我的职业目标是调查HLHS和先天性心血管畸形的原因。 K08将提供必要的分子遗传学培训，以实现这些目标。 Lifton博士是心血管遗传学及其他的公认的领导者。指导是我职业发展的重要组成部分。 耶鲁大学的儿科和遗传学部门结合了Lifton实验室的广泛资源，为获得启动我的研究职业所需的调查技能提供了理想的环境。 该奖项为发展我的职业生涯提供了所有重要组成部分，并将最大程度地发挥我的学业潜力。