Characterization of a Novel Mouse Model for Fuchs Endothelial Corneal Dystrophy

• DOI: 10.1167/iovs.65.4.18
• Publication Date: 2024-04-08T13:31:09Z
• Authors: Subashree Murugan; Viviane Souza de ...; Sachin Anil Ghag; Matthew Ng; Rajalekshmy Shyam
• Keywords: 0301 basic medicine; Symporters; Fuchs' Endothelial Dystrophy; Anion Transport Proteins; Endothelial Cells; Cornea; Mice; Disease Models, Animal; Tamoxifen; 0302 clinical medicine; Animals; Lactic Acid

AbstractPurposeFuchs Endothelial Corneal Dystrophy (FECD) is a progressive blinding disorder prevalent in 4% of Americans over 40. Corneal transplantation is the standard treatment. Animal models with partial FECD features exist, but a model encompassing all the major disease characteristics is desirable to improve the understanding of the pathogenesis and to identify signaling pathways involved in the disease onset and progression. Such an animal model can be helpful to develop intervention strategies. Here, we developed a mouse model that recapitulates all the features of FECD.MethodLoss of function mutations inSlc4a11and a knock-in mutation inCol8a2(Q455K) are implicated in FECD. Mice with Slc4a11 and Col8a2 mutations in C57BL/6J background were crossed to generate double mutant mice at F2 generation. At five weeks of age, a subset of the animals were fed tamoxifen-enriched chow or standard chow for two weeks, followed by standard chow. Corneal thickness, endothelial cell density, and guttae were measured at 5 (baseline) and 16 weeks of age. Corneas collected from mice at 16 weeks were stained for tight and adherens junctions, and reactive oxygen species. A lactate assay was performed to evaluate the endothelial pump function.ResultsThe double mutant tamoxifen-fed mice showed increased corneal thickness, decreased endothelial cell density, presence of guttae, and elevated stromal lactate levels. The endothelial cells showed altered morphology with disrupted adherens junctions and elevated ROS.ConclusionOverall, this mouse model recapitulates all the important phenotypic features associated with FECD.