Developmental and genetic function of SHROOM3

SHROOM3的发育和遗传功能

• 批准号: 10587298
• 负责人: Stephanie M Ware
• 金额: $ 53.09万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587298
• 关键词: Actomyosin; Address; Animal Model; Apical; Binding; Biological Assay; Cause of Death; Cell Lineage; Cell Polarity; Cells; Child; Congenital Abnormality; Congenital Heart Defects; Cytoskeleton; Data; Defect; Development; Developmental Biology; Disease susceptibility; Embryonic Heart; Etiology; Exhibits; Family; Frequencies; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Genomics; Heart Abnormalities; Heterozygote; Human; Human Genetics; Immunoprecipitation; In Vitro; Indiana; Investigation; Knowledge; Lead; Link; Mass Spectrum Analysis; Movement; Mus; Mutate; Mutation; Outcome; Pathway interactions; Patients; Pediatric Cardiac Genomics Consortium; Penetrance; Phenocopy; Phenotype; Predisposition; Prognosis; Proteins; Rho-associated kinase; Role; Shapes; Signal Pathway; Signal Transduction; Technology; Testing; Tissues; Translating; Variant; Ventricular Septal Defects; Xenopus; biobank; cardiogenesis; cell motility; cohort; congenital heart disorder; constriction; developmental genetics; disease phenotype; exome; exome sequencing; functional genomics; genetic architecture; genetic testing; genetic variant; genome sequencing; genome wide association study; human disease; human genomics; human model; improved; in vivo; member; mouse model; novel; planar cell polarity; protein protein interaction; public health relevance; rare variant; risk prediction; single-cell RNA sequencing; transcriptome sequencing; whole genome

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.

项目概要 先天性心脏病（CHD）是出生缺陷导致的最常见死亡原因。尽管其频率很高， 确定冠心病的遗传原因一直具有挑战性。散发性（非综合征性）先心病的孟德尔遗传 是罕见的。相反，先心病的遗传结构具有非外显性、可变表达性和 可能的寡基因效应。尽管全基因组关联研究、三重奏和基于家族的研究已经 使用时，很少强调检查上位性、附加效应或突变负担。 此外，尽管对心脏发育的了解有所提高，已经确定了基因和途径 在动物模型中，这些知识是先心病的基础，但这些知识并不总是能轻易转化为对 人类冠心病的致病原因。为了提高我们预测冠心病风险和预后的能力， 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非常重要 通过发育生物学进行变异分析，以实现机制理解。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 和轮廓来满足关键需求 其相互作用组，作为利用人类基因组学和发育生物学的范例。本次活动的目的 研究目的是：1）检验心脏发生需要 SHROOM3 与平面细胞极性相互作用的假设 (PCP) 蛋白和下游效应子。这一目标的结果将确定细胞和组织特异性 Shroom3 缺失的后果，确定其相互作用组及其遗传相互作用对 CHD 的影响； 2) 检验编码 PCP 信号和下游效应蛋白的基因中存在罕见变异的假设 CHD 患者体内含量丰富。这一目标的结果将在功能上验证 SHROOM3 罕见变体 并确定对冠心病易感性重要的基因和途径。使用功能组合 基因组学来定义罕见变异的影响，使用小鼠模型进行机制研究，以及人类遗传学， 这些研究将共同​​定义 SHROOM3 在心脏发育中的作用以及 CHD 遗传结构的 SHROOM3 和 PCP 通路成员。