Forward Genetics to Identify Complex Gene Interactions Involved in Glaucoma

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DESCRIPTION (provided by applicant): This application is in response to (08) Genomics 09-EY-101: Genomics of complex eye diseases. Using forward genetics in zebrafish and pedigree/patient DNA sequence analysis in humans, we will identify complex genetic interactions that contribute to phenotypes associated with primary open angle glaucoma. The glaucomas are a group of vision impairing diseases characterized by retinal ganglion cell death, and frequently associated with elevated intraocular pressure. Glaucoma is the second leading cause of blindness world-wide, with a prevalence of approximately 1.0% overall. However, specific groups including aged individuals, African-Americans, and those with myopia are at greater risk. For example, for individuals over 40 years of age the incidence of glaucoma is 1.9%. The incidence increases further to 3.5% in people over 70 years of age. The complex nature and limits of traditional genetic approaches in humans and mammalian model systems has prevented the identification of most genes that impact glaucoma. Over the past few years we have developed methodologies and tools in zebrafish to detect and measure glaucoma-associated phenotypes in both larval and aged zebrafish. Zebrafish show similar ocular anatomy and physiology to humans and are highly amenable to large-scale forward genetic screens to identify genes and signaling pathways that affect normal homeostasis or cause disease. In the current study we propose a genetic screen in adult zebrafish to identify mutants that display anterior segment dysgenesis, elevated intraocular pressure, and/or retinal ganglion cell degeneration. We will then use these mutants to identify the causative loci for each mutation. Finally, we will investigate whether any of the genes PUBLIC HEALTH RELEVANCE: The proposal outlines a genetic screen in zebrafish for mutations that result in aged adult onset glaucoma associated phenotypes. The screen takes advantage of an existing zebrafish mutation we recently identified that has non-pathological raised intraocular pressure. This mutation functions as a sensitized background or "pre-disposed condition" that will aid in identifying new mutations that result in blinding degenerations. We will follow this screen by identifying the affected genes and performing a more detailed phenotype characterization for each mutation. Finally, identified genes will be used to address whether othologous loci are affected in human glaucomas.