PURPOSE: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. METHODS: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). RESULTS: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. CONCLUSIONS: This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

California Northstate University College of Medicine Elk Grove California United States

Chair of Experimental Genetics TUM School of Life Sciences Technische Universität München Freising Germany

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 252 50 Vestec Czech Republic

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

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 California United States

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

Department of Surgery School of Medicine University of California Davis Sacramento California United States

Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California Davis Davis California United States

German Center for Diabetes Research Neuherberg Germany

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 United Kingdom

Mouse Biology Program University of California Davis Davis California United States

RIKEN BioResource Research Center Tsukuba Japan

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

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

The Jackson Laboratory Bar Harbor Maine United States

The Wellcome Trust Sanger Institute Wellcome Genome Campus Hinxton Cambridge United Kingdom

Touro University California College of Osteopathic Medicine Vallejo California United States

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 California United States

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