Funding outcome

Our overall research goal is to understand the genetic and cellular causality of pediatric blinding disorders. Our primary research interest (funded by CIHR) is to investigate mechanisms underlying the etiology of birth defects affecting the eye. During embryonic development, a fissure forms in the eye that functions to allow nascent blood vessels to grow into the eye. This fissure is transient and upon closure, the retina and iris are once again contiguous. In patients born with ocular coloboma, the fissure fails to close and a portion of the retina or iris remain open. This deformation in retina and/or iris frequently afflicts the optic nerve and leads to approximately 11% of pediatric blindness. In recent years, we have identified a subset of patients with ocular coloboma with atypical coloboma alignment. The ocular fissure is present in the inferior eye (at the equivalent of 6 o'clock) and coloboma patients typically present with openings that are similarly located in the bottom of their eye. We have now identified seven patients who possess ocular coloboma oriented toward the top portion of the eye. This 'superior coloboma' defines a novel birth defect and study of genetic causality of this birth defect is the focus of our CIHR grant. We have utilized zebrafish to demonstrate that there is a novel fissure in the dorsal (upper) portion of the retina, aligning precisely with the position of patient superior coloboma. We have recently used exome sequencing to uncover alterations to superior coloboma patient genomes. Such studies have uncovered mutations in genes already implicated in other aspects of retinal development. The goal for Maria's summer project is to test the hypothesis that mutations in one such gene are likely pathogenic. She will study two models in which gene function is altered, mimicking either the patient mutation or a loss of gene function. By studying the embryonic shaping of the eye in such animal models, she will be able to ascertain whether this gene has a critical function in superior fissure closure and if the mutation is likely to cause an alteration to biological activity. Such research will lay the foundation for understanding the genetic and cellular mechanisms that cause the novel birth defect superior coloboma.