Interrogation and Interpretation of Common Fund Data Sets to Identify Novel Ocular Disease Genes - Project Summary/Abstract Inherited diseases are a major source of blindness. These diseases are typically single-gene disorders. Some may cause developmental defects in early eye formation, others cause the degeneration of photoreceptor cells, while others may cause anterior segment disease. Historically they have been classified based on the clinical phenotype and then grouped into various disease entities. Retinitis pigmentosa (RP), an example of a rod-cone dystrophy, is the most common form of inherited retinal disease. It has a constellation of classical findings observed on eye examination accompanied by progressive loss of rod and then cone photoreceptors leading to eventual blindness in late stages of the disease. In the past three decades the genetic basis of many forms of inherited retinal diseases, for example, have been discovered leading to the identification of over 270 retinal disease genes. Mutations of over 80 genes are known to be associated with RP alone. However, in spite of the tremendous progress that has been made, the identification of the causative genetic alteration can be identified in only 50-75% of patients with presumed inherited retinal disease, even after whole genome sequencing. Based on this fact, it is presumed that significant numbers of unknown ocular disease genes exist. One approach to identify additional ocular disease genes in the mammalian retina is to take advantage of knockout mouse technology. The Knockout Mouse Phenotyping (KOMP) program is part of the International Mouse Phenotyping Consortium (IMPC), a group of scientists from mouse clinics around the world with the common goal of creating single gene knockout mice for every gene in the mouse genome. To date, over 7,000 single gene knockout mice have been created and phenotyped of the ~24,000 protein coding genes in the mouse genome. The UC Davis Mouse Biology Program is one of just three KOMP/IMPC centers in the US and generates a large number of knockout mice for the KOMP pipeline. Mouse knockouts receive comprehensive phenotyping in every organ system in the first four months of life prior to necropsy and histopathology. Knockout lines are annotated for dozens of specific eye abnormalities which are carefully documented during the phenotyping process. Identification of ocular disease genes in knockout mice provides candidate eye disease genes relevant in people. This proposal seeks to close the gap on the remaining 25-50% of patients with presumed inherited ocular diseases that currently cannot be genetically diagnosed. In this project we will identify all mouse retinal disease genes identified by the KOMP. In addition, we will correlate these novel mouse ocular disease genes for human relevance by cross referencing with the GTEx data base, also supported by the Common Fund. Furthermore, we will deeply analyze the specific cell biology of novel genes, by literature search, Gene Ontology, Panther Pathway, STRING, Syscilia, CiliaCarta, and publicly available ophthalmic GWAS. This proposal will catalyze discoveries and generate novel hypotheses based on clinically relevant pathways previously unimplicated in eye disease.
