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 导致显着发病率和死亡率的常见人类畸形 除了巨大的社会和经济成本。出生缺陷登记 表明先天性心脏缺陷的发生率约为 1% 人类的谎言分娩和 10% 的死产 (1)。过去30年 心脏疾病的诊断和治疗取得了重大进展 婴儿和儿童的缺陷。人们对正常情况知之甚少 指导人类心脏形态发生的分子信号或途径，也不 这些过程有时会如何以及为什么会失败。人类遗传的应用 分析对遗传性先天性心脏病的研究具有巨大的意义 有潜力为这些复杂的人类过程提供新颖的见解。 该应用的重点是定义分子原因 遗传性人类先天性心脏缺陷。 研究人员最近发现了三个导致人类 心脏畸形。 (1) 映射到t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 导致骨骼和室间隔缺损以及窦或房间隔缺损 室间隔缺损、窦房结或房室结缺损 独立于间隔缺陷而出现的异常）。 (2) 的 研究人员最近绘制了导致非综合征的基因缺陷图谱 继发孔房间隔缺损伴房室传导 染色体 5q 的延迟，并证明了该基因的因果基因 位点为 Nkappax2.5（也称为 hCSx）。 (3) 调查人员已 确定了 5p 号染色体上的一个位点，该位点可导致非综合征性继发孔心房 无传导缺陷的间隔缺损。受影响的个人 5q 和 5p 位点突变可能具有正常的心脏结构、心房 间隔动脉瘤、二叶式主动脉瓣、持续性左上腔 静脉，或更复杂的结构缺陷（例如法洛四联症）。 这种可变的表达性与这些基因的外显率降低相结合 突变部分掩盖了家族（和遗传）性质 这些先天性心脏缺陷。 研究人员的数据和其他人的研究清楚地表明遗传 人类先天性心脏病的异质性。进一步鉴定 已知疾病基因和尚未发现的疾病基因突变的特征 因此，定义应该能够更好地理解人类 心脏形态发生和心脏畸形的分子基础。 具有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 这些研究还可能提高对非家族性的理解 先天性心脏病。 研究人员建议通过以下方式解决这些问题 具体目标：（1）进一步表征临床表现 人类 TBX5 和 Nkappax2.5 突变阐明结构/功能 关系； (2) 识别其他导致遗传的基因缺陷 使用定位克隆和候选基因治疗心脏畸形 分析； (3) 设计并表征具有人类 TBX5 突变的小鼠 其他心脏畸形基因； (5) 检验假设 TBX5 是 在某些细胞中受到等位基因排斥。