GENETIC ANALYSIS OF INHERITED CONGENITAL HEART DISEASES

(改编自申请人的摘要)先天性心脏病是 常见的人类畸形，导致严重的发病率、死亡率、 此外还有巨大的社会和经济成本。出生缺陷登记处 约1%的人会发生先天性心脏病 人类的胎生和10%的死产(1)。在过去30年里 在心脏的诊断和治疗方面取得了重大进展 婴儿和儿童的缺陷。人们对正常情况的了解要少得多 指导人类心脏形态发生的分子信号或途径，也不 这些过程有时会失败的原因和原因。人类遗传学的应用 遗传性先天性心脏病的研究分析具有巨大的现实意义 有可能为这些复杂的人类过程提供新的见解。 本应用程序的重点是定义 遗传性人类先天性心脏病。 研究人员最近确定了三个导致人类 心脏畸形。(1)定位于T染色体的Holt-Oram综合征 12q2是由人类TBX5基因突变引起的。这种先天畸形 导致骨骼和室间隔缺损以及窦道或房室- 室间隔缺损、窦道或房室结 独立于间隔缺陷出现的异常)。(2) 研究人员最近定位了导致非综合征的基因缺陷 继发孔型房间隔缺损合并房室传导 延迟到染色体5q，并在此证明了原因基因 基因座为Nkappax2.5(也称为hCSx)。(3)调查人员有 确定了染色体5p上导致非综合征继发孔房颤的基因 无传导缺陷的室间隔缺损。受影响的个人 5q和5p基因座的突变可能具有正常的心脏结构 室间隔瘤、二尖瓣、永存左上静脉 腔静脉或更复杂的结构缺陷(如法洛四联症)。 这种可变的表现力与这些基因外显率的降低相结合 突变已经部分地掩盖了家族性(和遗传性) 这些先天心脏缺陷。 研究人员的数据和其他人的研究清楚地证明了基因 人类先天性心脏病的异质性。进一步识别 以及已知和尚未发现的疾病基因突变的特征 因此，应该提供对人类更好的理解 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发展和特征 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族性疾病的认识。 先天性心脏病。 调查人员建议通过以下方式解决这些问题 具体目标：(1)进一步描述本病的临床表现 人类Tbx5和Nkappax2.5突变以阐明结构/功能 关系；(2)确定导致可遗传的其他基因缺陷 心脏畸形定位克隆及候选基因的研究 分析；(3)设计和鉴定具有人类TBX5突变的小鼠 其他心脏畸形基因；以及(5)检验TBX5是 在某些细胞中易受等位基因排斥。

(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.