GENETIC ANALYSIS OF INHERITED CONGENITAL HEART DISEASES

遗传性先天性心脏病的基因分析

• 批准号: 6589052
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 29.3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589052
• 关键词: clinical research; congenital heart disorder; developmental genetics; disease /disorder model; gene expression; gene mutation; gene targeting; genetic regulation; genetic screening; genetically modified animals; genotype; human genetic material tag; human subject; laboratory mouse; linkage mapping; model design /development; molecular cloning; molecular genetics; phenotype; polymerase chain reaction; protein structure function; transcription factor; yeast two hybrid system

(Adapted from the Applicant's Abstract) Congenital heart defects are common human malformations that cause significant morbidity, mortality, in addition to substantial social and economic costs. Birth defect registries indicated congenital heart defects occur in approximately 1 percent of human lie births and 10 percent of stillbirths (1). Over the past 30 years major advances have occurred in the diagnosis and management of heart defects in infants and children. Far less is known about the normal molecular signals or pathways that direct human cardiac morphogenesis, nor how and why these processes sometimes fail. Application of human genetic analysis to the study of inherited congenital heart disease has enormous potential to provide novel insights into these complex human processes. The focus of this application is to define the molecular causes of inherited human congenital heart defects. The investigators have recently identified three loci that cause human cardiac malformations. (1) Holt-Oram syndrome which maps tot chromosome 12q2 is caused by mutations in human TBX5. This congenital malformation causes skeletal and ventricular septal defects and sinus or atrio- ventricular septal defects, and sinus or atrio-ventricular nodal abnormalities that arise independent of septation defects). (2) The investigators have recently mapped gene defects that cause non-syndromic secundum atrial septal defects with associated atrioventricular conduction delays to chromosome 5q and have demonstrated the causal gene at this locus to be Nkappax2.5 (also termed hCSx). (3) The investigators have defined a locus on chromosome 5p that causes non-syndromic secundum atrial septal defects without conduction defects. Individuals affected by mutations in the 5q and 5p loci may have normal cardiac structure, atrial septal aneurysm, bicuspid aortic valve, persistent left superior vena cava, or more complex structural defects (such as tetralogy of Fallot). This variable expressivity combined with reduced penetrance of these gene mutations have partially obscured the familial (and genetic) nature of these congenital heart defects. The investigators' data and studies by others clearly demonstrate genetic heterogeneity of human congenital heart disease. Further identification and characterization of mutations in known disease genes and those yet to be defined should therefore provide a better understanding of human cardiac morphogenesis and the molecular basis of cardiac malformations. Development and characterization of animal models with these mutations should help explain the variable expression of these mutations. Ultimately these studies may also improve the understanding of non-familial congenital heart disease. The investigators propose to address these issues through the following specific aims: (1) characterize further the clinical manifestations of human TBX5 and Nkappax2.5 mutations to elucidate structure/function relationships; (2) identify other gene defects that cause heritable cardiac malformations using positional cloning and candidate gene analyses; (3) engineer and characterize mice with human TBX5 mutations in other cardiac malformation genes; and (5) test the hypothesis that TBX5 is subject to allelic exclusion in some cells.

（改编自申请人的摘要）先天性心脏缺陷是 常见的人类畸形引起明显的发病率，死亡率， 补充大量的社会和经济成本。先天缺陷注册表 指示的先天性心脏缺陷大约发生 人类谎言出生和死产的10％（1）。在过去的30年中 心脏诊断和管理发生了重大进展 婴儿和儿童的缺陷。关于正常的知之甚少 指导人类心脏形态发生的分子信号或途径 这些过程的方式和原因有时会失败。人类遗传的应用 分析对遗传先天性心脏病的研究具有巨大 潜力提供对这些复杂人类过程的新见解。 该应用的重点是定义 继承的人类先天性心脏缺陷。 研究人员最近确定了三个引起人类的基因座 心脏畸形。 （1）映射染色体的Holt-Oram综合征 12q2是由人类TBX5突变引起的。这种先天性畸形 导致骨骼和心室间隔缺陷以及窦或肌 心室间隔缺陷，窦或心室鼻腔淋巴结 与分隔缺陷无关的异常。 （2） 研究人员最近绘制了引起非综合征的基因缺陷 与室内室内传导的secundum心房间隔缺陷 延迟到5q染色体，并在此证明了因果基因 位点为nkappax2.5（也称为HCSX）。 （3）调查人员有 定义了5P染色体上的基因座 没有传导缺陷的间隔缺陷。受到影响的个人 5q和5p基因座的突变可能具有正常的心脏结构，心房 隔膜动脉瘤，双尖瓣主动脉瓣，持续的左上静脉 CAVA或更复杂的结构缺陷（例如Fallot的四边形）。 这种变量表达性结合了这些基因的渗透率降低 突变部分掩盖了家族性（和遗传）的性质 这些先天性心脏缺陷。 研究人员的数据和其他研究清楚地证明了遗传 人类先天性心脏病的异质性。进一步识别 以及已知疾病基因中突变的表征 因此，被定义应提供对人类的更好理解 心脏形态发生和心脏畸形的分子基础。 使用这些突变的动物模型的开发和表征 应该有助于解释这些突变的可变表达。最终 这些研究也可能提高对非家庭的理解 先天性心脏病。 调查人员建议通过以下 具体目的：（1）进一步表征 人类TBX5和NKAPPAX2.5突变以阐明结构/功能 关系； （2）识别导致遗传的其他基因缺陷 使用位置克隆和候选基因的心脏畸形 分析； （3）工程师并用人类TBX5突变的小鼠来表征 其他心脏畸形基因； （5）检验TBX5是 在某些细胞中不受等位基因排除。