This is a multiple PI R21 application to test the hypothesis that trinucleotide repeat (TNR) expansion plays a role in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD), a common, autosomal dominant, late-onset eye disease. Corneal edema due to FECD is the most common indication for corneal transplantation in the United States. There are no known medical therapies to halt disease progression, and the pathogenesis is not well understood. Our previous work has identified a TGC TNR expansion in the transcription factor 4 (TCF4) gene as the most robust biomarker for the disease, being present in ~80% of cases and in 3% of controls. We now have preliminary data suggesting that transcripts from the TCF4 repeat expansion form RNA foci in corneal endothelial cells from FECD patients. This finding is analogous to myotonic dystrophy, type 1 (DM1) in which an identical trinucleotide expansion in the 3' untranslated region of a protein kinase gene leads to aggregation of the transcribed repeat sequence into characteristic nuclear RNA foci, which sequester the critical splicing factor muscleblind-like 1 (MBNL1). In DM1 the reduction in effective MBNL1 levels alters the patterns of mRNA splicing of numerous transcripts, contributing to the spectrum of clinical findings in the disease. We propose to test the hypothesis that expansion of CTG repeats in TCF4 similarly alters splicing patterns in the corneal endothelium from FECD patients. Secondary objectives will include analysis of the effect of TCF4 repeat expansion on gene expression profiles and the relationship between such widespread changes in the genomic architecture of corneal endothelial cells and disease progression in FECD. Our unifying hypothesis is that FECD is a TNR expansion disease. Mechanistically, we hypothesize that the disease results from both qualitative and quantitative effects of TNR expansion on gene expression in the corneal endothelium (CE). To address this issue, we will analyze mRNA expression patterns in diseased and normal human CE to determine how gene expression patterns are altered in FECD patients. Relevance Preliminary experiments suggest the hypothesis that FECD is the most common TNR expansion disease described to date. If the proposed experiments support this hypothesis, it will provide insight int pathogenic mechanisms and suggest novel approaches for treating FECD. There is no plausible way to reverse TNR expansion, so our hope for novel therapies depends upon detailing the molecular basis of FECD pathogenesis. We hope to eventually identify therapeutic targets to mitigate disease progression and reduce the need for corneal transplants.
Fuchs endothelial corneal dystrophy (FECD) is a serious eye disease with a clear genetic basis, but little is known about how specific genetic variants contribute to the development of disease. Our data suggest that the expansion of a CTG sequence in the TCF4 gene is the major contributor to disease in the Caucasian population. The work proposed here will test the hypothesis that the major mechanism for pathogenesis is RNA toxicity, a recently described process involving the disruption of normal cellular gene expression by aggregated RNA molecules containing the expanded repeats. We expect to identify common key biochemical pathways critical in the pathogenesis of FECD. This information will help guide investigations to identify targets for medical or novel therapies as an alternative to the only available current treatment, allogeneic transplantation.
| Soragni, Elisabetta; Petrosyan, Lina; Rinkoski, Tommy A et al. (2018) Repeat-Associated Non-ATG (RAN) Translation in Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 59:1888-1896 |
| Wieben, Eric D; Aleff, Ross A; Tang, Xiaojia et al. (2017) Trinucleotide Repeat Expansion in the Transcription Factor 4 (TCF4) Gene Leads to Widespread mRNA Splicing Changes in Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 58:343-352 |
| Mahr, Michael A; Baratz, Keith H; Hodge, David O et al. (2016) Racial/Ethnic Differences in Rates of Penetrating or Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy Among US Medicare Beneficiaries. JAMA Ophthalmol 134:1178-1180 |
