Developmental and genetic function of SHROOM3

项目摘要 先天性心脏病（CHD）是由于出生缺陷导致死亡的最常见原因。尽管它的频率， 确定冠心病的遗传原因一直是一个挑战。散发性（非综合征性）CHD的孟德尔遗传 是罕见的。相反，CHD的遗传结构的特点是非特异性，可变的表达性， 可能是寡基因效应。虽然全基因组关联研究，三人组和基于家庭的研究已经被 利用，很少强调检查上位性，加性效应，或突变负担。 此外，尽管对心脏发育的进一步了解已经确定了基因和途径， 在动物模型中，这些知识并不总是容易转化为对冠心病的理解， 人类CHD的病因。为了提高我们预测冠心病风险和预后的能力， 重要的是要确定新的基因和途径，有助于散发性冠心病和整合功能基因组学 用发育生物学进行变异分析，以了解机制。我们建议解决这些问题 通过研究引起心脏畸形的新基因SHROOM 3和描绘的关键需求 作为利用人类基因组学和发育生物学的典范。其目的是 研究是：1）测试心脏发生需要SHROOM 3与平面细胞极性相互作用的假设 (PCP)蛋白质和下游效应物。这一目标的结果将确定细胞和组织特异性 Shroom 3缺失的后果，鉴定其相互作用组及其对CHD的遗传相互作用的后果; 和2）测试编码PCP信号传导和下游效应蛋白的基因中的罕见变体 在冠心病患者中富集。这一目标的结果将在功能上验证SHROOM 3罕见变体 并确定对冠心病易感性重要的基因和途径。使用函数的组合 基因组学，以确定罕见变异的影响，使用小鼠模型的机制研究，和人类遗传学， 这些研究将共同确定SHROOM 3在心脏发育中的作用， SHROOM 3和PCP通路成员与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.