PURPOSE: Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans. METHODS: 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P < 0.0001) abnormal cornea morphology to identify candidate CD genes. Corneal abnormalities were investigated by histopathology. A literature search was used to determine the proportion of candidate genes previously associated with CDs in mice and humans. Phenotypes of human orthologues of mouse candidate genes were compared with known human CD genes to identify protein-protein interactions and molecular pathways 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. RESULTS: Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes. Of these, 37 (17%) genes were previously known to be associated with CD, including 14 in the mouse, 16 in humans, and 7 in both. The remaining 176 (83%) genes have not been previously implicated in CD. We also searched publicly available RNAseq data and found that 131 of the total 213 (61.5%) were expressed in adult human corneal tissue. STRING analysis showed several interactions within and between candidate and established CD proteins. All cellular pathways of the established genes were found in the PANTHER analysis of the candidate genes. Several of the candidate genes were implicated in corneal disease, such as TGF-ß signaling. We also identified other possible underappreciated mechanisms relevant to the human cornea. CONCLUSIONS: We identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not previously been implicated in corneal pathology. Bioinformatic analyses implicated candidate genes in several signaling pathways which are potential therapeutic targets.

California Northstate University College of Medicine Elk Grove CA USA

College of Veterinary Medicine Seoul National University Seoul Republic of Korea

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Integrative Physiology Baylor College of Medicine Houston TX USA

Department of Laboratory Medicine and Pathobiology Faculty of Medicine University of Toronto Toronto ON Canada

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Department of Molecular and Life Science Hanyang University Seoul Republic of Korea

Department of Ophthalmology and Vision Science School of Medicine University of California Davis Sacramento CA USA

Department of Ophthalmology Institute of Vision Research Yonsei University College of Medicine Seoul Republic of Korea

Department of Pathology Microbiology and Immunology School of Veterinary Medicine University of California Davis Sacramento CA USA

Department of Surgery School of Medicine University of California Davis Sacramento CA USA

Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California Davis Davis CA USA

Institute of Developmental Genetics Helmholtz Zentrum München Neuherberg Germany

Institute of Experimental Genetics German Mouse Clinic Helmholtz Zentrum München Neuherberg Germany

Laboratory Animal Center Korea Research Institute of Bioscience and Biotechnology Daejeon Republic of Korea

Laboratory of Developmental Biology and Genomics Research Institute of Veterinary Science BK21 Plus Program for Advanced Veterinary Science College of Veterinary Medicine and Interdisciplinary Program for Bioinformatics Seoul National University Seoul Republic of Korea

Mary Lyon Centre Medical Research Council Harwell Institute Harwell UK

Medical Research Council Harwell Institute Harwell UK

Mouse Biology Program University of California Davis Davis CA USA

RIKEN BioResource Research Center Tsukuba Japan

The Centre for Phenogenomics Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Toronto ON Canada

The Centre for Phenogenomics The Hospital for Sick Children Toronto ON Canada

The Jackson Laboratory Bar Harbor ME USA

The Wellcome Trust Sanger Institute Wellcome Genome Campus Hinxton Cambridge UK

Touro University California College of Medicine Vallejo CA USA

UC Davis Eye Center 4860 Y St Ste Sacramento CA 2400 95817 USA

Université de Strasbourg CNRS Inserm IGBMC UMR 7104 UMR S 1258 Illkirch F 67400 France

Université de Strasbourg CNRS UMR 7104 INSERM U 1258 IGBMC Institut Clinique de la Souris PHENOMIN Illkirch Graffenstaden France

University of California Davis School of Medicine Sacramento CA USA

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