A DROSOPHILA MODEL FOR CORNELIA DE LANGE SYNDROME

描述（由申请人提供）：根据孟德尔遗传模式对罕见的多系统遗传疾病进行定位克隆，可以识别在人类发育中起关键作用的基因和分子途径。虽然疾病基因鉴定对受罕见人类疾病影响的家庭的影响是巨大的，但这些发现的真正力量更多地来自于它们对更常见的、往往是孤立的人类结构发育缺陷的发病机制提供的见解，而这些缺陷的基因更难以绘制。我们最近发现，NIPBL突变导致Cornelia de Lange综合征（CdLS），这是一种显性遗传发育障碍，为识别伴随这种诊断（颅面、肢体、胃肠、心脏、泌尿生殖系统等）的多种结构和发育缺陷相关的下游遗传靶点提供了起点。NIPBL在哺乳动物中的功能在很大程度上是未知的，然而在果蝇中的研究表明，它的同源基因Nipped B调节内聚蛋白复合物，并通过这种功能控制远程增强子-启动子相互作用。自确定NIPBL为CdLS疾病基因以来，所有项目负责人都积极参与了富有成效的合作，该项目项目建立在项目负责人的优势、经验和资源基础上。PI和项目负责人将共同系统地研究NIPBL，其相互作用蛋白和下游靶基因，并表征该基因和途径对人类结构性出生缺陷的影响。在人类（项目一）、小鼠和斑马鱼（项目二）和果蝇（项目三）中研究该基因和通路的三管齐下方法将协同表征NIPBL及其下游靶点在引起综合征和孤立的人类结构性出生缺陷中的功能、相互作用和作用。该项目将得到一个数据和资源共享核心的支持，该核心将为所有三个项目提供动力，而一个行政核心将监督、促进和优化所有项目的相互作用。外行语言：Cornelia de Lange综合征（CdLS）是一种由NIPBL突变引起的多系统发育障碍，NIPBL是一种通过远程增强子-启动子相互作用调节下游基因的新基因。本提案概述了一项计划，以表征NIPBL的功能，确定其靶基因，并评估其在导致CdLS中所见的孤立结构性出生缺陷类型中的作用。

DESCRIPTION (provided by applicant): Positional cloning of rare multisystem genetic disorders that follow Mendelian inheritance patterns allows for the identification of genes and molecular pathways that play critical roles in human development. While the impact of disease gene identification on families affected by rare human disorders is tremendous, the true strength of these discoveries comes more from the insight they provide into the pathogenesis of more common and often isolated human structural developmental defects, the genes for which are much more difficult to map. Our recent discovery that mutations in NIPBL cause Cornelia de Lange syndrome (CdLS), a dominantly inherited genetic developmental disorder, provides a starting point to identify downstream genetic targets that are involved in the multiple structural and developmental defects that accompany this diagnosis (craniofacial, limb, gastrointestinal, cardiac, genitourinary and others). The function of NIPBL in mammals is largely unknown, however work in Drosophila has shown that its homolog Nipped B regulates the cohesin complex, and through this function controls long range enhancer-promoter interactions. This program project builds on the strengths, experience and resources available to the project leaders, all of whom have been actively involved in a fruitful collaboration since the identification of NIPBL as the CdLS disease gene. The PI and project leaders will work together to sytematically study NIPBL, its interacting proteins and downstream target genes and to characterize the effects this gene and pathway has on human structural birth defects. A three-pronged approach to studying this gene and pathway in humans (Project I), mouse and zebrafish (Project II) and Drosophila (Project III) will synergistically characterize the function, interactions and role of NIPBL and its downstream targets in causing syndromic and isolated human structural birth defects. This project will be supported by a data- and resource-sharing core that will fuel all three projects and an adminsitrative core to oversee and facilitate and optimize the interactions of all projects. Lay Language: Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder caused by mutations in NIPBL, a novel gene involved in regulating downstream genes through long-range enhancerpromoter interactions. This proposal outlines a plan to characterize NIPBL's function, identify its target genes and evaluate their role in causing isolated structural birth defects of the types seen in CdLS.