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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Zuin, Jessica; Franke, Vedran; van Ijcken, Wilfred F J et al. (2014) A cohesin-independent role for NIPBL at promoters provides insights in CdLS. PLoS Genet 10:e1004153
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Schaaf, Cheri A; Misulovin, Ziva; Gause, Maria et al. (2013) Cohesin and polycomb proteins functionally interact to control transcription at silenced and active genes. PLoS Genet 9:e1003560

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