Genome-wide screening reveals the genetic basis of mammalian embryonic eye development
Chee, Justine M. (Oakland University William Beaumont)
Lanoue, Louise (University of California Davis)
Clary, Dave (University of California Davis)
Higgins, Kendall (University of Miami)
Bower, Lynette (University of California Davis)
Flenniken, Ann (Lunenfeld-Tanenbaum Research Institute. Sinai Health (Canada))
Guo, Ruolin (The Hospital for Sick Children (Canada))
Adams, David J. (Wellcome Trust Sanger Institute (Regne Unit))
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Braun, Robert E. (The Jackson Laboratory)
Brown, Steve D. M. (Medical Research Council Harwell Institute (UK))
Chin, Hsian-Jean Genie (National Applied Research Laboratories. National Laboratory Animal Center (Taiwan))
Dickinson, Mary E. (Baylor College of Medicine. Department of Molecular and Human Genetics)
Hsu, Chih-Wei (Baylor College of Medicine. Department of Molecular and Human Genetics)
Dobbie, Michael (The John Curtin School of Medical Research (Australia))
Gao, Xiang (Nanjing University. Nanjing Biomedical Research Institute)
Galande, Sanjeev (Indian Institutes of Science Education and Research)
Grobler, Anne (PCDDP North-West University (South Africa))
Heaney, Jason D. (Baylor College of Medicine. Department of Molecular and Human Genetics)
Herault, Yann (Université de Strasbourg. Institut de Génétique et de Biologie Moléculaire et Cellulaire)
De Angelis, Martin Hrabe (Helmholtz Zentrum München. Institute of Experimental Genetics)
Mammano, Fabio (Italian National Research Council (Italy))
Nutter, Lauryl M. J. (The Hospital for Sick Children (Canada))
Parkinson, Helen (European Bioinformatics Institute (UK))
Qin, Chuan (National Laboratory Animal Center. National Applied Research Laboratories (China))
Shiroishi, Toshi (RIKEN BioResource Center (Japan))
Sedlacek, Radislav (Institute of Molecular Genetics of the Czech Academy of Sciences. Czech Center for Phenogenomics)
Seong, J-K (Seoul National University. Research Institute for Veterinary Science)
Xu, Ying (Soochow University. CAM-SU Genomic Resource Center)
Brooks, Brian (National Eye Institute. Ophthalmic Genetics and Visual Function Branch (USA))
McKerlie, Colin (University of Toronto. Department of Laboratory Medicine & Pathobiology)
Lloyd, K. C. Kent (University of California Davis. Department of Surgery, School of Medicine)
Westerberg, Henrik (Medical Research Council Harwell Institute (UK))
Moshiri, Ala (UC Davis Eye Center (USA))

Date:	2023
Abstract:	Background: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Results: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17. 0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Conclusions: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	MAC spectrum ; Eye development ; Mouse ; IMPC ; Serine-glycine biosynthesis ; CPLANE
Published in:	BMC biology, Vol. 21 (February 2023) , art. 22, ISSN 1741-7007

DOI: 10.1186/s12915-022-01475-0
PMID: 36737727

15 p, 2.1 MB

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