Studies on the pathogenesis of CHARGE syndrome

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CHARGE syndrome is an autosomal dominant malformation syndrome. It was postulated, that most features seen in CHARGE syndrome patients are due to abnormalities in neural crest development. By performing a genome-wide microarray expression analysis on wild-type and Chd7 deficient mouse embryos (at day 9.5) we could identify many Chd7 target genes, with functions in neural crest cell development and migration. Therefore, objectives in the here presented proposal are the analysis of the molecular pathomechanisms in Chd7 deficient neural crest cells and the identification of regulatory networks. The identification of regulatory networks, CHD7 regulated key genes and their specific correction could be important aspects for the establishment of therapeutic options. We already performed functional analysis for the CHD7 regulated chemoattractant molecule Sema3a. These studies lead to the hypothesis that Sema3a act as a modifier in the pathogenesis of CHARGE syndrome. Therefore, we would like to clarify this hypothesis by performing experiments on mouse embryos, cell culture studies and a SEMA3A mutational screening in mild and severely affected CHARGE syndrome patients carrying a CHD7 mutation.