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. ? ? ? ?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Javois, Lorette Claire
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital of Philadelphia
United States
Zip Code
Mills, Jason A; Herrera, Pamela S; Kaur, Maninder et al. (2018) NIPBL+/- haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states. Sci Rep 8:1056
Newkirk, Daniel A; Chen, Yen-Yun; Chien, Richard et al. (2017) The effect of Nipped-B-like (Nipbl) haploinsufficiency on genome-wide cohesin binding and target gene expression: modeling Cornelia de Lange syndrome. Clin Epigenetics 9:89
Muto, Akihiko; Schilling, Thomas F (2017) Zebrafish as a Model to Study Cohesin and Cohesinopathies. Methods Mol Biol 1515:177-196
Kline, Antonie D; Krantz, Ian D; Deardorff, Matthew A et al. (2017) Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016. Am J Med Genet A 173:1172-1185
Kawauchi, Shimako; Santos, Rosaysela; Muto, Akihiko et al. (2016) Using mouse and zebrafish models to understand the etiology of developmental defects in Cornelia de Lange Syndrome. Am J Med Genet C Semin Med Genet 172:138-45
Kaur, Maninder; Mehta, Devanshi; Noon, Sarah E et al. (2016) NIPBL expression levels in CdLS probands as a predictor of mutation type and phenotypic severity. Am J Med Genet C Semin Med Genet 172:163-70
Mehta, Devanshi; Vergano, Samantha A Schrier; Deardorff, Matthew et al. (2016) Characterization of limb differences in children with Cornelia de Lange Syndrome. Am J Med Genet C Semin Med Genet 172:155-62
Santos, Rosaysela; Kawauchi, Shimako; Jacobs, Russell E et al. (2016) Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLoS Biol 14:e2000197
Dorsett, Dale (2016) The Drosophila melanogaster model for Cornelia de Lange syndrome: Implications for etiology and therapeutics. Am J Med Genet C Semin Med Genet 172:129-37
Lopez-Burks, Martha E; Santos, Rosaysela; Kawauchi, Shimako et al. (2016) Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet 172:146-54

Showing the most recent 10 out of 72 publications