Cornelia de Lange Syndrome (CdLS) is an autosomal dominant multisystem developmental disorder characterized by facial dysmorphism, hirsutism, upper limb abnormalities, cognitive retardation, and growth abnormalities. Over 50% of cases are associated with mutations in the NIPBL gene resulting in NIPBL haploinsufficiency. NIPBL (Nipbl in mice) is required for loading of the essential multiprotein complex """"""""cohesin"""""""" onto chromatin. Cohesin functions in sister chromatid cohesion important for mitosis and DNA repair as well as in developmental gene regulation. Nipbl haploinsufficiency causes reduction of cohesin binding to chromatin, which is not sufficiently severe to disrupt sister chromatid cohesion, but does compromise long- range chromatin interactions resulting in alteration of gene expression. It is thought that the Nipbl deficiency generates the clinical features of the disorder primarily through reduced cohesin loading onto chromatin. However, how Nipbl determines the specific loading sites for cohesin in developmental gene regulation and whether it has any additional functions in the cell have not been investigated. We found that Nipbl localizes to the nucleolus and affects ribosomal RNA (rRNA) biosynthesis. Abnormalities in nucleolar function and ribosome biogenesis are known to cause phenotypically similar human developmental disorders with growth and mental retardation, and are thus termed """"""""ribosomopathies"""""""". It is possible therefore that CdLS is also a ribosomopathy. Importantly, we obtained evidence that Nipbl is an RNA-binding protein and that it associates with the ribosomal DNA (rDNA) region in an RNA-dependent manner. This suggests that RNA is an important mediator of Nipbl function, which may represent a cohesin-independent function and/or may contribute to determining the specificity of cohesin binding to particular genomic regions. Thus, we plan to characterize the RNA-binding activity and nucleolar function of Nipbl and examine their significance in relationship to cohesin function and CdLS pathogenesis, using both human cells and a Nipbl+/- mouse model. The goal of the project is to better understand the CdLS disease mechanism in order to develop a rational approach to potential therapeutic interventions.

Public Health Relevance

Cornelia de Lange Syndrome (CdLS) is an autosomal dominant multisystem developmental disorder whose underlying pathogenic mechanism remains unclear. Since most CdLS cases result from Nipbl haploinsufficiency, it is essential to understand the role of Nipbl in this disorder's pathogenesis. In the proposed project, we plan to test the hypothesis that the disease is caused in part by dysregulation of nucleolar activity mediated by Nipbl, and to address the role of RNA in Nipbl function. The outcome of this study should provide new insight into the molecular events at the root of CdLS, which may lead to the possible development of new therapeutic strategies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Molecular Genetics A Study Section (MGA)
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Oster-Granite, Mary Lou
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University of California Irvine
Schools of Medicine
United States
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