Defining the genetic interaction between CHD7 and semaphorin signalling by exploring C.Elegans as animal model

CHARGE syndrome (CS) is a rare genetic disease, mainly due to mutations of the chromatin remodeller gene CHD7 and characterized by multiple developmental malformations. These include eye coloboma, heart defects, choanal atresia, reproductive defects, developmental delay and deafness. No pharmacological treatments are available and the affected individuals, mainly children, display high phenotypic variability and severity of the symptoms. A possible explanation of this heterogeneity, is that mutations in other genes with an epistatic relationship to CHD7 may function as ‘modifiers’ to alter the expressivity of disease traits in the context of CHD7 aploinsufficiency. Several are the evidences from other researchers and from our pilot data indicating that the genes encoding emaphorins and their receptors might be good candidates as CHD7 genetic interactors. Thus, for this grant proposal, we wish to combine for the first time in the field an unparalleled series of C.elegans mutants with a drug screening and mouse cell lines to reveal he genetic interactions between CHD7 and semaphorins and to identify novel potential pharmacological targets. This knowledge will be undamental to plan future therapies aimed at bypassing CHD7 deficiency in CS-patients.