NIPBL, Cohesin and Related Structural Birth Defects

描述（由申请方提供）：对遵循孟德尔遗传模式的罕见多系统遗传性疾病进行定位克隆，可以识别在人类发育中发挥关键作用的基因和分子通路。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且往往是孤立的人类结构发育缺陷的发病机制的洞察，这些缺陷的基因更难以定位。我们最近发现，NIPBL突变导致科尔内利亚德兰格综合征（CdLS），一种显性遗传性遗传发育障碍，提供了一个起点，以确定下游的遗传目标，参与多种结构和发育缺陷，伴随着这种诊断（颅面，肢体，胃肠道，心脏，泌尿生殖系统和其他）。NIPBL在哺乳动物中的功能在很大程度上是未知的，然而在果蝇中的工作表明，其同源物Nipped B调节粘附素复合物，并通过该功能控制长距离增强子-启动子相互作用。该计划项目建立在项目负责人的优势，经验和资源的基础上，自NIPBL被确定为CdLS疾病基因以来，所有人都积极参与了富有成效的合作。PI和项目负责人将共同研究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I），小鼠和斑马鱼（项目II）和果蝇（项目III）中研究该基因和途径的三管齐下的方法将协同表征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，还将得到一个行政核心的支持，以监督、促进和优化所有项目的互动。Lay语言：科尔内利亚德兰格综合征（CdLS）是由NIPBL基因突变引起的一种多系统发育障碍。该提案概述了一项计划，以表征NIPBL的功能，确定其靶基因，并评估其在引起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.