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.
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