Identification of Novel Genes Required for Eye Function via Systematic Screening of Knockout Mouse Lines by the International Mouse Phenotyping Consortium

Abstract

Purpose : To identify genes required for normal ocular development and function. Determining the genetic basis of eye development and function remains a major challenge in the diagnosis and treatment of both common and rare blinding diseases. This process requires a spectrum of approaches from human clinical genetics to the utilization of model organisms to direct scientists to potential disease loci. In this manuscript we report a large-scale genetic screen in mice using a phenotype-driven discovery strategy to identify genes required for normal eye function.

Methods : Forward systematic ophthalmic screening of single-gene targeted knockout mouse pipelines across several international sites to pinpoint genes required for various components of ocular anatomy and function. We performed complete ocular examination of all knockout mice produced at the Mouse Biology Program at UC Davis. To maximize the ocular phenotypes detected through all collaborative branches of this knockout mouse project, we interrogated the public data base at www.mousephenotype.org to include all animals with eye related phenotypes.

Results : In summary, we have identified 470 unique genes required for eye development and function. Of these, 308 have no known role in the eye in any species, and are therefore novel. Another 104 genes are known to be expressed in ocular tissues, but are not associated with a known ocular phenotype. The remaining 58 genes have established ocular phenotypes in humans, mice, fish, or other vertebrates. Each of these genes affects one or more ocular structures. The genes have been organized based on the structure(s) affected in the eye.

Conclusions : These genes reveal a number of new molecular pathways potentially involved in human ocular development and disease. We illustrate examples of knockout mouse phenotypes discovered in the screen affecting various compartments of the eye.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.