Cornelia de Lange Syndrome (CdLS) is a multi-organ system constellation of birth defects caused by dysfunction of cohesin, a protein complex required for chromosome cohesion, and recently implicated in the regulation of gene expression. This work will continue the development and analysis of two animal models of A//pib/-deficiency, the most common genetic cause of CdLS. The Nipbl+I- mouse replicates many features of CdLS including a high frequency of cardiac septal abnormalities. The A//pW-morphant zebrafish also displays cardiac defects, as well as gut defects that are typical of CdLS. In both systems, Nipbl deficiency appears to cause hundreds of relatively small, often tissue-specific, changes in gene expression, just as has been seen in cell lines from individuals with CdLS. The goal of the proposed work is to exploit the mouse and fish models to (1) understand the origins of heart defects in CdLS, and (2) determine the extent to which major structural defects in CdLS have a combinatorial etiology-i.e. arise as the result of synergistic interactions among small changes in the expression of multiple genes.
The first aim will be accomplished using newly-developed transgenic mouse lines that harbor conditional/invertible (FLEx) alleles of Nipbl, which may be successively toggled from functionally-mutant to wildtype, and back again to mutant. Using these mouse lines, the timing and cell type(s) of origin of cardiac septal defects will be pinpointed, and potentially causal changes in gene expression identified.
The second aim will be accomplished using a zebrafish model of CdLS. Experiments in this aim will focus on the identification of new potential Nipbl "target" genes, and the quantitative manipulation of their expression during early embryogenesis. Accomplishing these aims should not only aid in understanding, treating and/or preventing birth defects in CdLS;it is also likely to provide novel insights into the origins of non-syndromic birth defects, which are much more common, but may also frequently result from combinatorial interactions among small-effect alleles in the general population.

Public Health Relevance

The impact of structural birth defects on human health is enormous. Animal models of Cornelia de Lange Syndrome (CdLS) will be exploited to generate new insights into the origins of birth defects, especially those of the heart and gut. Because of the way the gene defect underlying this syndrome works, there is a good probability that the results obtained will be directly relevant to common causes of birth defects in the general population.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD052860-09
Application #
8608564
Study Section
Special Emphasis Panel (ZHD1-DSR-N)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
$541,289
Indirect Cost
$39,149
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Muto, Akihiko; Ikeda, Shingo; Lopez-Burks, Martha E et al. (2014) Nipbl and mediator cooperatively regulate gene expression to control limb development. PLoS Genet 10:e1004671
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
Krantz, Ian D (2014) Cohesin embraces new phenotypes. Nat Genet 46:1157-8
Visnes, T; Giordano, F; Kuznetsova, A et al. (2014) Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I. Chromosoma 123:239-52
Dorsett, Dale; Kassis, Judith A (2014) Checks and balances between cohesin and polycomb in gene silencing and transcription. Curr Biol 24:R535-9
Kaiser, Frank J; Ansari, Morad; Braunholz, Diana et al. (2014) Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Hum Mol Genet 23:2888-900
Slavin, Thomas P; Krantz, Ian (2013) Response to "germline mosaicism in Cornelia de Lange syndrome: dilemmas and risk figures" by Mariani et al. Am J Med Genet A 161A:1827
Jyonouchi, Soma; Orange, Jordan; Sullivan, Kathleen E et al. (2013) Immunologic features of Cornelia de Lange syndrome. Pediatrics 132:e484-9
Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina et al. (2013) Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome. Hum Mutat 34:1589-96
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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