The long term goal of this Program is to elucidate the manner in which disruption of normal cohesin function results in the multisystem developmental disorder Cornelia de Lange syndrome (CdLS) and to identify downstream effectors of cohesin function that are important in the pathogenesis of more common isolated birth defects of the types (e.g. congenital heart defects, cleft palate, diaphragmatic hernias, limb defects) seen in constellation in CdLS. The PI (Dr. Krantz) and Project Leaders (Dr. Lander and Dr. Dorsett) of this Program established a successful collaboration since the Pi's discovery of the first CdLS gene (NIPBL) and the initial implication of cohesin in human developmental disorders. At the inception of this Program the role of NIPBL and cohesin in mammalian development was largely unknown. Dr. Dorsett's discovery that the NIPBL ortholog in Drosophila (nipped-b) was a key regulator of gene expression, prompted the initial hypothesis that disruption of cohesin's non-canonical role in gene regulation was the underlying mechanism involved in causing CdLS. This Program Project has built, and will continue to build, on the diverse, but complementary, strengths, experience and resources available to the project leaders. A three-pronged approach to studying this gene and pathway in humans (Project I), mouse and zebrafish (Project II) and Drosophila (Project III) has led to significant discoveries into how cohesin and its regulators function, the identification of novel CdLS genes, the characterization of a group of developmental disorders collectively termed """"""""cohesinopathies"""""""", as well as the establishment of valuable resources including the only Nipbl mutant mouse model, multiple mutant Drosophila lines and the world's largest repository of cohesin mutant human cell lines and clinical information. In this renewal our collaborative team will use innovative approaches to continue to synergistically characterize the function, interactions and role of the structural and regulatory cohesin proteins involved in CdLS, and their downstream targets, in causing syndromic and isolated human structural birth defects. This Program is supported by a data- and resource-sharing core that will fuel all three Projects and an administrative core to oversee, facilitate and optimize the interactions of all Projects.

Public Health Relevance

CdLS is a multisystem developmental disorder caused by mutations in structural and regulatory cohesin genes. Recent discoveries have identified a non-canonical role of cohesin as a critical regulator of gene expression, disruption of which results in significant developmental consequences. This Program outlines a plan to characterize cohesin's function in gene regulation, identify its effector genes and evaluate their role in causing isolated 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)
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Special Emphasis Panel (ZHD1-DSR-N (KJ))
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Javois, Lorette Claire
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Children's Hospital of Philadelphia
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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

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