Developmental and genetic function of SHROOM3

项目总结 先天性心脏病(CHD)是最常见的出生缺陷死亡原因。尽管频率很高， 识别先天性心脏病的遗传原因一直是具有挑战性的。散发性(非综合征)冠心病的孟德尔遗传 是很罕见的。相反，CHD的遗传结构的特征是非外显性、可变的表现力和 可能的寡聚效应。尽管全基因组关联研究、三联组研究和基于家庭的研究 利用，很少强调检查上位性、加性效应或突变负担。 此外，尽管对心脏发育的更好的理解已经确定了基因和途径 动物模型中CHD的基础，这种知识并不总是容易地转化为对 人类冠心病的病因分析。为了提高我们预测冠心病风险和预后的能力， 重要的是识别导致散发性冠心病的新基因和途径，并整合功能基因组学 用发育生物学进行变异体分析，以便从机制上理解。我们建议解决这些问题 通过研究导致心脏畸形的新基因SHROOM3的关键需求和描述 作为利用人类基因组学和发育生物学的典范。这样做的目的是 研究的目的是：1)验证心脏发生需要SHROOM3与平面细胞极性相互作用的假设 (PCP)蛋白和下游效应物。这一目标的结果将确定细胞和组织的特异性 Shroom3缺失的后果，确定其相互作用组及其遗传交互作用在CHD中的后果； 2)检验编码PCP信号和下游效应蛋白的基因罕见变异的假设 在冠心病患者中是富含的。这一目标的结果将从功能上验证SHROOM3罕见的变体 并确定与冠心病易感性有关的重要基因和途径。使用功能组合 基因组学来定义稀有变异的影响，使用小鼠模型的机制研究，以及人类遗传学， 这些研究将共同确定SHROOM3在心脏发育中的作用以及 SHROOM3和PCP途径成员与CHD的遗传结构

PROJECT SUMMARY Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite its frequency, identifying genetic causes of CHD has been challenging. Mendelian inheritance of sporadic (nonsyndromic) CHD is rare. Instead, the genetic architecture of CHD is characterized by non-penetrance, variable expressivity, and likely oligogenic effects. Although genome wide association studies, trio, and family-based studies have been utilized, there has been little emphasis on examining epistasis, additive effects, or mutational burden. Furthermore, although an improved understanding of cardiac development has identified genes and pathways that underlie CHD in animal models, this knowledge has not always translated readily into an understanding of disease causation in human CHD. In order to improve our ability to predict risk for CHD and prognosis, it is important to identify new genes and pathways that contribute to sporadic CHD and integrate functional genomics for variant analysis with developmental biology for mechanistic understanding. We propose to address these critical needs through investigation of a novel gene causing cardiac malformations, SHROOM3, and delineation of its interactome, as an exemplar leveraging human genomics and developmental biology. The aims of this study are to: 1) test the hypothesis that cardiogenesis requires SHROOM3 interaction with planar cell polarity (PCP) proteins and downstream effectors. The outcome of this aim will identify cell- and tissue-specific consequences of loss of Shroom3, identify its interactome and consequence of its genetic interactions on CHD; and 2) test the hypothesis that rare variants in genes encoding PCP signaling and downstream effector proteins are enriched in patients with CHD. The outcome of this aim will functionally validate SHROOM3 rare variants and identify genes and pathways important for the susceptibility to CHD. Using a combination of functional genomics to define the impact of rare variants, mechanistic studies using mouse models, and human genetics, these studies will collectively define the role of SHROOM3 in heart development and the contribution of SHROOM3 and PCP pathway members to the genetic architecture of CHD.