Age-related Corneal Disease Mediated by Expanded CUG Repeat RNA

Presented on September 8th, 2023.

Vinod Mootha, MD
University of Texas Southwestern Medical Center, Dallas, Texas, United States

Fuchs endothelial corneal dystrophy (FECD) is an age-related degenerative eye disease that impacts up to 4% of United States population. Seventy percent of cases are caused by an intronic trinucleotide repeat expansion in the TCF4 gene. While corneal transplants are a useful treatment, pharmacological interventions would likely have an important impact on patient care. Successful drugs will require a better understanding of the molecular, cellular, and phenotypic consequences of the disease. Here we examine those consequences in adjacent eye tissues beyond the corneal endothelium: lens epithelium, corneal epithelium, corneal stroma, and trabecular meshwork. Expanded CUG repeat RNA nuclear foci, the hallmark of FECD in corneal endothelium, are rare in corneal epithelium and stroma, and absent in lens epithelium. By contrast, we observe higher numbers of foci in the trabecular meshwork, a key tissue involved in glaucoma. With few exceptions including mis-splicing in trabecular meshwork, differential gene expression and splicing changes associated with the expanded repeat in corneal endothelial cells are not observed in other cell types. Expression of the TCF4 transcripts including full length isoforms containing the repeat sequence at the 5’ end is much higher in corneal endothelium or trabecular meshwork than in corneal stroma or corneal epithelium. Expression of the CUG repeat containingTCF4 transcripts is higher in corneal endothelium, likely contributing to foci formation and the large molecular and pathologic impact on those cells.

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