Mutant mouse genetic modifications have revolutionized biomedical research, enabling scientists to study specific gene mutations and their effects on biological processes. This study used data mining to investigate congenital abnormalities underlying the Microphthalmia, Anophthalmia, and Coloboma (MAC) spectrum disease, a group of eye malformations that cause childhood visual impairment.
The research involved a systematic forward screening of the mammalian genome, using the International Mouse Phenotyping Consortium (IMPC) database to identify knockout lines with genetically associated eye defects in mouse embryos. The IMPC database is a valuable resource for researchers, as it contains a vast array of information on knockout mouse models and associated phenotypes.
Data mining efforts identified 74 unique knockout lines (genes) with ocular abnormalities, most of which were small or absent eyes - findings most relevant to MAC spectrum disease in humans. Of these 74 lines, 27 had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. This left 12 previously published gene knockouts with no reported ocular abnormalities and 47 unpublished knockouts with ocular abnormalities identified by the IMPC. These represented 59 genes not previously associated with early eye development in mice.
Further analysis identified 19 of these genes with a reported human eye phenotype, demonstrating the clinical relevance of our findings. In total, 40 previously unimplicated genes linked to mammalian eye development were identified, highlighting the power of mutant mouse genetic modifications in identifying novel gene targets for rare diseases.
Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Notably, 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.
The findings provide a valuable resource for researchers investigating the genetic abnormalities underlying MAC spectrum disease and other congenital blinding diseases. Using data mining and mutant mouse genetic modifications, novel genes and pathways required for early eye development are open for further research application. These findings can potentially accelerate the diagnosis and treatment of these rare diseases.
Chee, J.M., Lanoue, L., Clary, D. et al. Genome-wide screening reveals the genetic basis of mammalian embryonic eye development. BMC Biol 21, 22 (2023).