Date of Award
Doctor of Philosophy (PhD)
Inherited retinal degenerative diseases are one of the leading causes of childhood blindness. While over 200 causative genes have been identified, many cases still have an unknown underlying genetic cause. With the advent of next generation sequencing (NGS), it should be possible to identify the genetic cause in almost every case, provided enough relatives are willing to participate. However, the massive amount of data generated by NGS can make identifying the pathogenic variant challenging. It is necessary to filter the data in order to create a manageable candidate list, but overly strict filtering or erroneous assumptions can result in filtering out the pathogenic variant. Identifying the genetic cause of retinal degeneration in each patient will allow us to better identify candidate genes for gene therapy and bring us a step closer to precision medicine. Here we developed an efficient screening system to find candidate mutations with minimal assumptions to avoid screening out pathogenic variants and better identify good candidates for novel gene discovery. Out of an initial cohort of 69 patients we identify the pathogenic variant(s) in 44 of them and identified 11 subjects as good candidates for novel gene discovery.
We also need a broad treatment for retinal degeneration to help those who have mutations in genes that are poor candidates for gene therapy or who have an unknown genetic cause. We tested the efficacy of using the GRM6 minimal promoter as a bipolar cell specific promoter to express channelrhodopsin in bipolar cells after photoreceptor degeneration to make the bipolar cells directly respond to light. Surprisingly, we found that unlike in the wildtype mouse retina, the GRM6 promoter is not bipolar cell specific in multiple mouse models of retinal degeneration. This suggests that the genetic profiles of the cells in the inner retina change during retinal degeneration. Understanding these fundamental changes in cell specific gene expression during retinal degenerative processes will be critical in order to develop effective therapeutic strategies for late stage retinal degeneration.
Bryant, Laura Mary, "Genetics And Retinal Degeneration: Challenges In Optogenetic Therapy And Indentifying Pathogenic Variants" (2017). Publicly Accessible Penn Dissertations. 2988.