Funding outcome

Known from ancient times - first mentioned in the old testament - Coloboma is a birth defect resulting in a hole in the lower portion of the retina or iris and causing in congenital blindness. In recent years, the Waskiewicz and Lehmann laboratories at the University of Alberta have identified five Edmonton patients with a novel form of Coloboma affecting the upper aspect of the eye, now entitled 'Superior Coloboma.' Utilizing zebrafish as a model system, we demonstrated that the upper portion of the embryonic eye contains a fissure, and that failure to close this fissure results in a colobomatous phenotype resembling superior coloboma patients. Analysis of superior coloboma patient genome sequences led to identification of rare variants that might result in this disorder. The goal of this proposed research project is to determine whether such variants cause superior coloboma in patients. To·accomplish this, we will create zebrafish strains that lack the two genes implicated and analyze embryonic development of the upper portion of the eye. In addition, we will create constructs that mimic the patient variants and use zebrafish to determine whether such alterations result in detectable changes in function. Such aims will elucidate the genetic causality of this novel blinding birth defect. The final component of our research is to develop potential methods to provide future patients with therapeutics. To this end, we will develop tools to perform genome editing in zebrafish strains that display superior coloboma. It is our strong opinion that such research will lay the foundation for experiments to repair this and many other childhood diseases.