Identification of apoptosis pathway in Treacher Collins Syndrome

Abstract

IDENTIFICATION OF APOPTOSIS PATHWAY IN TREACHER COLLINS SYNDROME By Khaled Alsayegh, B.S A Thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2009 Major Director: Rita Shiang Associate Professor, Department of Human & Molecular Genetics Treacher Collins Syndrome (TCS) is a rare autosomal dominant disorder characterized by severe craniofacial defects. The syndrome is associated with mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein called treacle. Model organisms have been generated to model the disease and have revealed knowledge about the etiology and pathogenesis of the disorder. The craniofacial abnormality observed in TCS patients is found to be caused by an increased level of apoptosis in the neuroepithelium and from this it has been suggested that treacle is important for proper formation and proliferation of neural crest cells that will ultimately contribute to the face. The best attempt to rescue the phenotype of TCS was made by inhibiting the expression of p53 in both zebrafish and mouse models. Although both rescues were successful, it resulted in tumor formation in mice which limits the potential of using this type of rescue in humans. Therefore, it is very important to identify p53-downstream genes that were not 5