Project I's long term goal is to fully characterize the genes that cause Cornelia de Lange Syndrome (CdLS) and to identify the downstream effectors of cohesin dysruption that are involved in the individual birth defects seen in constellafion in CdLS. This addresses the Program's long-term goals of explaining the efiology of CdLS and how that relates to more common isolated structural birth defects. CdLS is a dominant, genetically heterogeneous, developmental disorder consisting of pleiotropic manifestations. Characteristic features include craniofacial dysmorphia, reduction defects of the upper extremities, gastroesophageal, cardiac and ophthalmologic abnormalifies, growth retardation, and neurodevelopmental delay. We have shown that mutafions in genes encoding structural (SMC1A and SMC3) and regulatory (NIPBL) elements of cohesin cause CdLS. Cohesin is best understood for its canonical role in regulating sister chromatid cohesion and chromosome segregation, however its'less well understood role in gene regulation appears to be the crifical funcfion disrupted in CdLS. Since identificafion of cohesin's role in causing CdLS, mutafions in additional cohesin accessory factors (such as ESC02) have also been identified in human developmental disorders collectively termed """"""""cohesinopathies"""""""". We have shown that partial disruption of cohesin function leads to a highly conserved pattern of gene dysregulation in CdLS-derived cell lines. We hypothesize that heterozygous mutations in cohesin regulatory and structural components that result in CdLS cause a specific pattern of downstream gene dysregulation in a temporal and tissue-specific manner that in turn results in the individual birth defects seen in constellafion in CdLS. Identificafion of the downstream effectors of cohesin dysfuncfion will identify genes that are critical to these individual birth defects, such as limb defects, congenital heart defects, cleft palate and gastrointestinal abnormalifies. Through the 3 Specific Aims proposed in this project we will further characterize the role of cohesin in gene regulafion in humans, to understand how perturbation leads to CdLS, and to identify candidate genes that are regulated by cohesin that are important for the normal development of the structures that are affected in CdLS.

Public Health Relevance

Cornelia de Lange syndrome (CdLS) is a mulfisystem genetic disorder manifesfing manifold structural and cognitive abnormalities. This project will use cohesin mutant lymphoblastoid and induced pluripotent stem (IPS) cell lines established from individuals with CdLS to genomically characterize gene regulatory changes and identify candidate genes for isolated structural birth defects seen in constellation in CdLS. Informafion from these studies will lead to improved management for individuals with CdLS and related diagnoses.

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)
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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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