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.