Characterization of a novel Drosophila disease model for CHARGE Syndrome

Drexel University, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): CHARGE Syndrome (CS) is a rare, autosomal dominant disorder that is characterized by a variety of clinical symptoms. The most common of these include Coloboma, Choanal atresia, abnormal semicircular canals, heart defects, mental retardation, retardation of growth, and genital and ear anomalies, making CS a common cause of congenital anomalies. It is prevalent in approximately 1 in every 10,000 live births, and is caused in large part by loss of function mutations in the human Chd7 gene (haploinsufficiency in Chd7). Mutations in Chd7 account for some 2/3 of all patients diagnosed with CS, though little is known about the genes (and cellular processes) this protein regulates. The long term goal of this project is a deeper understanding of the mechanism(s) of pathogenesis of CS through characterization and application of a novel Drosophila model of the disease. Our hope is that research proposed here will ultimately lead to new diagnostic tools and/or therapeutic targets for treatment in patients with CS. Attempts to understand the complex etiology of many human diseases have been improved through the study of model organisms. The fruit fly, Drosophila melanogaster, has been tremendously important and influential in furthering our understanding of the mechanisms of a variety of human diseases. Using an RNA-interference (RNAi) gene knockdown strategy, we have created the first Drosophila model for CS in adult flies. Because kis, and its human homolog Chd7, encode transcription factors, the identification of biologically relevant target genes whose expression is regulated by these transcription factors, and whose function also contributes towards disease pathology will be critically required for a better understanding of this disease's pathogenesis, as well as a better rational design towards therapeutic intervention and/or diagnostic and prognostic indicators. As a model organism, Drosophila are unsurpassed as a tool of gene discovery and functional gene analysis. Using both genetic screening and microarray analysis in Drosophila, we have identified a number of target genes whose expression is regulated by kis function. Many of these target genes have the potential to contribute to one or more aspects of disease pathology. We wish to further test which of the genes that we have identified might contribute to specific aspects of disease pathology in CS through the following specific aim: to employ genetic, behavioral, and cell biological methods to further characterize which Kismet target genes may be biologically relevant to the disease symptoms observed in CS. We will specifically focus our analysis on gross motor dysfunction, intellectual disability, and defects in neuronal morphology. PUBLIC HEALTH RELEVANCE: The fruit fly, Drosophila melanogaster, has been tremendously important and influential in furthering our understanding of the mechanisms of a variety of human diseases, including neurodegenerative diseases, and forms of hereditary mental retardation (MR). Thus, we have created the first Drosophila model for CHARGE Syndrome, an uncommon autosomal dominant form of mental retardation. Using our new model, we will determine what genes functionally contribute to CHARGE Syndrome in flies, with the hope that the research proposed will lead to novel diagnostic tools and/or therapeutic targets for patients with CHARGE Syndrome.