Using Zebrafish Models of Usher Syndrome Type 2A to Investigate Retinal Cell Function and Survival

Abstract

Usher syndrome is the main cause of hereditary deaf-blindness. Patients diagnosed with Usher syndrome experience hearing loss and progressive blindness due to photoreceptor degeneration over several decades. The most common form of Usher syndrome, type 2A, is caused by mutations in the USH2A gene, which encodes the large protein Usherin. In this study, I characterized three different mutations affecting distinct regions of the zebrafish ush2a gene. In these mutant backgrounds, I studied the co-localization of other proteins known to interact with Usherin to test whether the loss of the normal Usherin protein disrupted localization of these other proteins. In humans, photoreceptor cell death takes place over many years, causing slow, progressive vision loss. The USH2A mouse model of Usher syndrome has a mild retinal phenotype compared to the degree of vision loss that human patients experience, perhaps due in part to their shorter lifespan. Zebrafish, similarly, have a much shorter lifespan than humans, so we devised a system that would challenge the retina with increased levels of light in an effort to accelerate the rate of photoreceptor damage. These studies have established a functional zebrafish model of USH2A induced Usher syndrome, which will provide researchers with a valuable tool for investigating treating the functional role of Usherin in vision and hearing, as well as providing a model for which to test new treatment options.