Abstract
Purpose :
There are currently no genetic models of late-onset Fuchs Endothelial Corneal Dystrophy (FECD), a complex disease of corneal edema and endothelial guttae which causes vision loss from the fifth decade of life. Such a mouse would be valuable to follow preclinical events, identify biomarkers, and test therapeutic interventions. We recreated, in mice, the heterozygous SLC4A11/W240S mutation (equivalent to W214S in the mouse protein) which causes late-onset FECD in humans.
Methods :
We backcrossed Slc4a11+/W214S mice to >99% isogeny with 129S wild-type (WT) mice. Corneal thickness (CT) was monitored bimonthly by ultrasonic pachymetry for 1 year in a cohort of 12 WT and 20 Slc4a11+/W214S mice. At the end of the trial, RNA was prepared from whole eyes from 4 female Slc4a11+/W214S mice and 3 female WT mice. RNA was evaluated by RNA sequencing and differential gene expression analysis (Azenta Life Sciences).
Results :
The CT of WT and Slc4a11+/W214S mice was not different at 2, 4, or 6 months (P>0.05), but was significantly thicker in Slc4a11+/W214S mice than in WT mice at 8, 10, and 12 months (P<0.01). At 12 months, the average CT ± SD was 122 ± 4 µm for WT mice (n=12) and 130 ± 6 µm for Slc4a11+/W214S mice (n=18). Of the 17,400 genes identified by RNAseq, only 11 were significantly downregulated in Slc4a11+/W214S mice. The most significantly and robustly altered gene in this set was the antioxidant long non-coding RNA Neat1 (log2foldchange = −1.3, padj = 2x10-6).
Conclusions :
Slc4a11+/W214S mice exhibit a progressive increase in CT consistent with late-onset FECD, perhaps at least in part directly due to loss of endothelial pump function caused by Slc4a11 insufficiency. However, the additional loss of Neat1 suggests an unexpected mechanism by which expressivity of late-onset FECD can be influenced by external factors, particularly oxidative damage. The work of others tells us two important things: [1] UVA exposure is sufficient to induce all signs of FECD including guttae (Liu et al., PNAS, 2020) and [2] Neat1 protects corneas from UVA-induced FECD (Wang et al., Mol Ther Nucleic Acids, 2022). Thus, the loss of Neat1 in Slc4a11+/W214S mice suggests that late onset of FECD in the proband with the SLC4A11/W240S mutation may be a combined consequence of SLC4A11 insufficiency as well as reduced protection from UVA-induced corneal damage.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.