PURPOSE: Analyze phenotypic data from knockout mice with late-adult retinal pathologic phenotypes to identify genes associated with development of adult-onset retinal diseases. METHODS: The International Mouse Phenotyping Consortium (IMPC) database was queried for genes associated with abnormal retinal phenotypes in the late-adult knockout mouse pipeline (49-80 weeks postnatal age). We identified human orthologs and performed protein-protein analysis and biological pathways analysis with known inherited retinal disease (IRD) and age-related macular degeneration (AMD) genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), PLatform for Analysis of single cell Eye in a Disk (PLAE), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: Screening of 587 late-adult mouse genes yielded 12 with abnormal retinal phenotypes, which corresponded to 20 human orthologs. Three of the 12 mouse genes and two of the 20 human orthologs were previously implicated in retinal pathology or physiology in a literature review. Although all of the genes demonstrated retinal pathology when deleted from the mouse genome, most do not have established roles in human retinal disease. Furthermore, human protein-protein analysis and biological pathway analysis yielded only a few relationships between the candidate gene list and that of known IRD and AMD genes, suggesting they may represent novel retinal functions. CONCLUSIONS: We identified 12 mouse genes with significant late-adult abnormal retinal pathology, eight of which have not been previously implicated in either mouse or human retinal physiology or pathology. These serve as novel retinal disease gene candidates for late-onset retinal disease.

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 Vestec Czech Republic

Department of Integrative Physiology Baylor College of Medicine Houston Texas United States

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

Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas United States

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

Department of Ophthalmology and Vision Science University of California Davis Eye Center Sacramento California United States

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 California United States

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

Developmental Genetics Munich School of Life Sciences Weihenstephan Technical University of Munich Freising Germany

German Center for Diabetes Research Neuherberg Germany

German Center for Mental Health Munich Augsburg Germany

German Center for Neurodegenerative Diseases Munich Germany

Institute of Developmental Genetics Helmholtz Munich 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

Medical Research Council Harwell Institute Harwell United Kingdom

Mouse Biology Program University of California Davis Davis California United States

Munich Cluster of Systems Neurology Munich Germany

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 Wellcome Trust Sanger Institute Wellcome Genome Campus Hinxton Cambridge United Kingdom

Université de Strasbourg CNRS Illkirch France

Université de Strasbourg CNRS INSERM CELPHEDIA PHENOMIN Institut Clinique de la Souris Illkirch Graffenstaden France

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