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Huan Meng, Mario Matthaei, Rhonda Grebe, Shukti Chakravarti, Albert Jun; L450W and Q455K Knock-In Mutations in the Col8a2 Gene Cause Fuchs Endothelial Corneal Dystrophy in the Mouse. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6600.
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Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal vision loss. The L450W and Q455K missense mutations in the alpha-2 collagen VIII encoding gene COL8A2 result in highly penetrant, early-onset disease. Here, we report two transgenic knock-in mouse lines, Col8a2L450W and Col8a2Q455K that closely recapitulate the corneal pathology of FECD.
In vivo endothelial cell counts, morphology, and Descemet membrane features were imaged and analyzed via confocal microscopy using the NIDEK Confocal Microscope. Ultrastructural analysis of endothelial cells and Descemets membrane was performed using transmission electron microscopy (TEM), and endothelial cell apoptosis was detected by TUNEL assay.
Col8a2 mutant mice showed enlarged, irregularly-shaped endothelial cells with excrescences of Descemet membrane (guttae) characteristic of FECD. In vivo confocal microscopy at 20 weeks revealed a 13% (p<.05) and 29% (p<.0001) decrease in endothelial cell counts in Col8a2L450W and Col8a2Q455K, respectively, compared to age-matched wild-type mice. 40-week-old mice demonstrated even greater cell loss, with Col8a2L450W and Col8a2Q455K having 30% (p<.0001) and 41% (p<.0001) fewer cells, respectively, than age-matched wild-type mice. Furthermore, we observed 20-week-old Col8a2 transgenic mice to have an average of 2.3±0.3 (n=26) TUNEL-positive cells per central corneal cross-section compared to 0.3±0.1 (n=19) in age-matched controls (p<.0001). TEM of corneas from transgenic mice revealed redundant, dilated endoplasmic reticulum consistent with the ultrastructural hallmarks of explanted FECD corneal tissues.
Taken together, these results suggest that missense mutations in murine Col8a2 lead to apoptosis, endothelial cell loss, and basement membrane alterations strikingly similar to human FECD. We conclude that Col8a2L450W and Col8a2Q455K transgenic mice represent important model systems in which future studies of the pathophysiology and potential therapies for FECD can be undertaken.
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