Systematic phenotyping of 8,000 knockout mouse lines identifies genes associated with abnormal corneal phenotypes

Abstract

Purpose : Corneal dystrophies (CDs) are eye disorders that affect the cornea. Currently, the genetic contribution of CDs remains incompletely understood. This study aims to identify individual genes as potential contributors to the development of CDs in humans.

Methods : The dataset of knockout mice produced by the International Mouse Phenotyping Consortium (IMPC) was queried for candidate CD genes associated with abnormal cornea phenotypes. A comprehensive literature search was used to determine if these candidate genes have been previously associated with CDs in mice and humans. The human orthologues of these candidate genes were compared with known human CD genes to identify potential mechanistic relationships. We looked for protein-protein interactions and molecular pathway functions using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes (KEGG).

Results : We identified 255 mouse lines with abnormal corneal morphology out of 8,267 total lines. Of these 255 genes, 21 were previously implicated in mouse corneal biology, and 24 were previously implicated in human corneal biology, with 5 genes overlapping. This left 215 genes previously unimplicated in corneal biology. Also, 154 genes were expressed in adult human corneal tissues. STRING analysis showed several interactions within and between mouse and human CD proteins. All cellular pathways of the known human CD gene set were found in the PANTHER analysis of the mouse candidate CD genes. Several candidate CD genes were implicated in pathways with established roles in CDs.

Conclusions : We identified 255 mouse genes that resulted in statistically significant corneal phenotypes in knockout mice. In our cornea literature search, 215 of these genes were not identified and may be previously unimplicated in corneal biology. Bioinformatic analyses suggest several common cellular functions between candidate and known CD genes. Furthermore, these analyses implicated candidate genes in TGF-Beta signaling, which is a known pathway implicated in corneal development and has been the target of corneal therapies. We also identified other cell-signaling pathways which may represent underappreciated mechanisms relevant to CDs.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.