Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes
Abstract 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...
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2025-01-01
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| author | Peter Vo Denise M. Imai-Leonard Benjamin Yang Andrew Briere Andy Shao M. Isabel Casanova David Adams Takanori Amano Oana Amarie Zorana Berberovic Lynette Bower Robert Braun Steve Brown Samantha Burrill Soo Young Cho Sharon Clementson-Mobbs Abigail D’Souza Mary Dickinson Mohammad Eskandarian Ann M. Flenniken Helmut Fuchs Valerie Gailus-Durner Jason Heaney Yann Hérault Martin Hrabe de Angelis Chih-Wei Hsu Shundan Jin Russell Joynson Yeon Kyung Kang Haerim Kim Hiroshi Masuya Hamid Meziane Steve Murray Ki-Hoan Nam Hyuna Noh Lauryl M. J. Nutter Marcela Palkova Jan Prochazka Miles Joseph Raishbrook Fabrice Riet Jennifer Ryan Jason Salazar Zachery Seavey John Richard Seavitt Radislav Sedlacek Mohammed Selloum Kyoung Yul Seo Je Kyung Seong Hae-Sol Shin Toshihiko Shiroishi Michelle Stewart Karen Svenson Masaru Tamura Heather Tolentino Uchechukwu Udensi Sara Wells Jacqueline White Amelia Willett Janine Wotton Wolfgang Wurst Atsushi Yoshiki The International Mouse Phenotyping Consortium Louise Lanoue K. C. Kent Lloyd Brian C. Leonard Michel J. Roux Colin McKerlie Ala Moshiri |
| author_facet | Peter Vo Denise M. Imai-Leonard Benjamin Yang Andrew Briere Andy Shao M. Isabel Casanova David Adams Takanori Amano Oana Amarie Zorana Berberovic Lynette Bower Robert Braun Steve Brown Samantha Burrill Soo Young Cho Sharon Clementson-Mobbs Abigail D’Souza Mary Dickinson Mohammad Eskandarian Ann M. Flenniken Helmut Fuchs Valerie Gailus-Durner Jason Heaney Yann Hérault Martin Hrabe de Angelis Chih-Wei Hsu Shundan Jin Russell Joynson Yeon Kyung Kang Haerim Kim Hiroshi Masuya Hamid Meziane Steve Murray Ki-Hoan Nam Hyuna Noh Lauryl M. J. Nutter Marcela Palkova Jan Prochazka Miles Joseph Raishbrook Fabrice Riet Jennifer Ryan Jason Salazar Zachery Seavey John Richard Seavitt Radislav Sedlacek Mohammed Selloum Kyoung Yul Seo Je Kyung Seong Hae-Sol Shin Toshihiko Shiroishi Michelle Stewart Karen Svenson Masaru Tamura Heather Tolentino Uchechukwu Udensi Sara Wells Jacqueline White Amelia Willett Janine Wotton Wolfgang Wurst Atsushi Yoshiki The International Mouse Phenotyping Consortium Louise Lanoue K. C. Kent Lloyd Brian C. Leonard Michel J. Roux Colin McKerlie Ala Moshiri |
| author_sort | Peter Vo |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-7346cc15ec8248fdb069983714a55d83 |
| institution | Kabale University |
| issn | 1471-2164 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj-art-7346cc15ec8248fdb069983714a55d832025-01-26T12:16:29ZengBMCBMC Genomics1471-21642025-01-0126111110.1186/s12864-025-11222-8Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypesPeter Vo0Denise M. Imai-Leonard1Benjamin Yang2Andrew Briere3Andy Shao4M. Isabel Casanova5David Adams6Takanori Amano7Oana Amarie8Zorana Berberovic9Lynette Bower10Robert Braun11Steve Brown12Samantha Burrill13Soo Young Cho14Sharon Clementson-Mobbs15Abigail D’Souza16Mary Dickinson17Mohammad Eskandarian18Ann M. Flenniken19Helmut Fuchs20Valerie Gailus-Durner21Jason Heaney22Yann Hérault23Martin Hrabe de Angelis24Chih-Wei Hsu25Shundan Jin26Russell Joynson27Yeon Kyung Kang28Haerim Kim29Hiroshi Masuya30Hamid Meziane31Steve Murray32Ki-Hoan Nam33Hyuna Noh34Lauryl M. J. Nutter35Marcela Palkova36Jan Prochazka37Miles Joseph Raishbrook38Fabrice Riet39Jennifer Ryan40Jason Salazar41Zachery Seavey42John Richard Seavitt43Radislav Sedlacek44Mohammed Selloum45Kyoung Yul Seo46Je Kyung Seong47Hae-Sol Shin48Toshihiko Shiroishi49Michelle Stewart50Karen Svenson51Masaru Tamura52Heather Tolentino53Uchechukwu Udensi54Sara Wells55Jacqueline White56Amelia Willett57Janine Wotton58Wolfgang Wurst59Atsushi Yoshiki60The International Mouse Phenotyping ConsortiumLouise Lanoue61K. C. Kent Lloyd62Brian C. Leonard63Michel J. Roux64Colin McKerlie65Ala Moshiri66California Northstate University College of MedicineDepartment of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California DavisUniversity of California Davis School of MedicineTouro University California College of MedicineDepartment of Ophthalmology & Vision Science, School of Medicine, University of California DavisDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California DavisThe Wellcome Trust Sanger InstituteRIKEN BioResource Research CenterInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum MünchenThe Centre for Phenogenomics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalMouse Biology Program, University of California DavisThe Jackson LaboratoryMedical Research Council, Harwell InstituteThe Jackson LaboratoryDepartment of Molecular and Life Science, Hanyang UniversityMary Lyon Centre, Medical Research Council, Harwell InstituteThe Centre for Phenogenomics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Integrative Physiology, Baylor College of MedicineThe Centre for Phenogenomics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalThe Centre for Phenogenomics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum MünchenInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum MünchenDepartment of Molecular and Human Genetics, Baylor College of MedicineUniversité de Strasbourg, CNRS UMR 7104, INSERM U 1258, IGBMC, Institut Clinique de la Souris, PHENOMINInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum MünchenDepartment of Integrative Physiology, Baylor College of MedicineRIKEN BioResource Research CenterMary Lyon Centre, Medical Research Council, Harwell InstituteCollege of Veterinary Medicine, Seoul National UniversityLaboratory Animal Center, Korea Research Institute of Bioscience and BiotechnologyRIKEN BioResource Research CenterUniversité de Strasbourg, CNRS UMR 7104, INSERM U 1258, IGBMC, Institut Clinique de la Souris, PHENOMINThe Jackson LaboratoryLaboratory Animal Center, Korea Research Institute of Bioscience and BiotechnologyCollege of Veterinary Medicine, Seoul National UniversityThe Centre for Phenogenomics, The Hospital for Sick ChildrenCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of SciencesCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of SciencesCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of SciencesUniversité de Strasbourg, CNRS UMR 7104, INSERM U 1258, IGBMC, Institut Clinique de la Souris, PHENOMINThe Jackson LaboratoryMouse Biology Program, University of California DavisThe Jackson LaboratoryDepartment of Molecular and Human Genetics, Baylor College of MedicineCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of SciencesUniversité de Strasbourg, CNRS UMR 7104, INSERM U 1258, IGBMC, Institut Clinique de la Souris, PHENOMINDepartment of Ophthalmology, Institute of Vision Research, Yonsei University College of MedicineLaboratory 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 UniversityDepartment of Ophthalmology, Institute of Vision Research, Yonsei University College of MedicineRIKEN BioResource Research CenterMary Lyon Centre, Medical Research Council, Harwell InstituteThe Jackson LaboratoryRIKEN BioResource Research CenterMouse Biology Program, University of California DavisDepartment of Integrative Physiology, Baylor College of MedicineMary Lyon Centre, Medical Research Council, Harwell InstituteThe Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryInstitute of Developmental Genetics, Helmholtz Zentrum MünchenRIKEN BioResource Research CenterMouse Biology Program, University of California DavisMouse Biology Program, University of California DavisDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California DavisUniversité de Strasbourg, CNRS, Inserm, IGBMC UMR 7104- UMR-S 1258The Centre for Phenogenomics, The Hospital for Sick ChildrenDepartment of Ophthalmology & Vision Science, School of Medicine, University of California DavisAbstract 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.https://doi.org/10.1186/s12864-025-11222-8Corneal dysmorphologiesCorneal diseaseCorneal dystrophies |
| spellingShingle | Peter Vo Denise M. Imai-Leonard Benjamin Yang Andrew Briere Andy Shao M. Isabel Casanova David Adams Takanori Amano Oana Amarie Zorana Berberovic Lynette Bower Robert Braun Steve Brown Samantha Burrill Soo Young Cho Sharon Clementson-Mobbs Abigail D’Souza Mary Dickinson Mohammad Eskandarian Ann M. Flenniken Helmut Fuchs Valerie Gailus-Durner Jason Heaney Yann Hérault Martin Hrabe de Angelis Chih-Wei Hsu Shundan Jin Russell Joynson Yeon Kyung Kang Haerim Kim Hiroshi Masuya Hamid Meziane Steve Murray Ki-Hoan Nam Hyuna Noh Lauryl M. J. Nutter Marcela Palkova Jan Prochazka Miles Joseph Raishbrook Fabrice Riet Jennifer Ryan Jason Salazar Zachery Seavey John Richard Seavitt Radislav Sedlacek Mohammed Selloum Kyoung Yul Seo Je Kyung Seong Hae-Sol Shin Toshihiko Shiroishi Michelle Stewart Karen Svenson Masaru Tamura Heather Tolentino Uchechukwu Udensi Sara Wells Jacqueline White Amelia Willett Janine Wotton Wolfgang Wurst Atsushi Yoshiki The International Mouse Phenotyping Consortium Louise Lanoue K. C. Kent Lloyd Brian C. Leonard Michel J. Roux Colin McKerlie Ala Moshiri Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes BMC Genomics Corneal dysmorphologies Corneal disease Corneal dystrophies |
| title | Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes |
| title_full | Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes |
| title_fullStr | Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes |
| title_full_unstemmed | Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes |
| title_short | Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes |
| title_sort | systematic ocular phenotyping of 8 707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes |
| topic | Corneal dysmorphologies Corneal disease Corneal dystrophies |
| url | https://doi.org/10.1186/s12864-025-11222-8 |
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