Identification and In Vivo Validation of Novel Genes for Developmental Glaucoma

Summary

Developmental glaucoma strikes early in life and can be caused by a congenital problem known as anterior segment dysgenesis (ASD), which is when the fluid-filled anterior segment of the eye doesn’t develop properly. One of the major consequences of ASD is glaucoma, which can lead to irreversible blindness at a young age. Our goal is to understand how these problems come about with the end goal of establishing treatments.

Project Details

The focus of this project is to identify and validate new genes that can cause malformations of the front of the eye that lead to glaucoma.

We are approaching this goal in three steps. First, we are sequencing the entire genomes of patients that have developmental glaucoma and using sophisticated computational tools to prioritize genetic variants that might be causing glaucoma in these patients. Next, to prove that the mutations that we identify are indeed involved in eye development, we will express the mutations in zebrafish to see if they also cause developmental defects in that model system. If they do, we will use these model organisms to try to understand how the mutant gene leads to glaucoma. Finally, for genes that are validated to be involved in eye development, we will sequence a large panel of other patients that have developmental glaucoma to try to understand what proportion of patients might be affected by mutations in the newly identified gene.

There are two unique aspects of our project. First, we are using 'whole genome sequencing' to identify genes that might cause glaucoma in patients. While many groups seek to identify novel genes by sequencing only the coding regions of the genome, we will examine the entire genome to identify mutations that may be overlooked using other methods. Second, we are employing cutting edge genome editing techniques to quickly and specifically recreate mutations in zebrafish to generate new research models.

Upon completion of this project, we will know more about the genes and cellular pathways that are disrupted in developmental glaucoma. Understanding how these pathways work is important because that opens the possibility that the pathway(s) can be restored or preserved to prevent or treat glaucoma in these patients.