The TCF4 Trinucleotide Repeat Expansion of Fuchs’ Endothelial Corneal Dystrophy: Implications for the Anterior Segment of the Eye

Abstract

Purpose In the United States, 70% of Fuchs’ endothelial corneal dystrophy (FECD) cases are caused by an intronic trinucleotide repeat expansion in the TCF4 gene. CUG repeat RNA transcripts from this expansion accumulate as nuclear foci in the corneal endothelium. In this study, we sought to detect foci in other anterior segment cell types and assess their molecular impact. Methods We examined CUG repeat RNA foci appearance, expression of downstream affected genes, gene splicing, and TCF4 RNA expression in corneal endothelium, corneal stromal keratocytes, corneal epithelium, trabecular meshwork cells, and lens epithelium. Results CUG repeat RNA foci, the hallmark of FECD in corneal endothelium (found in 84% of endothelial cells), are less detectable in trabecular meshwork cells (41%), much less prevalent in stromal keratocytes (11%) or corneal epithelium (4%), and absent in lens epithelium. With few exceptions including mis-splicing in the 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 the corneal endothelium or trabecular meshwork than in the corneal stroma or corneal epithelium. Conclusions Expression of the CUG repeat containing TCF4 transcripts is higher in the corneal endothelium, likely contributing to foci formation and the large molecular and pathologic impact on those cells. Further studies are warranted to examine any glaucoma risk and impact of the observed foci in the trabecular meshwork of these patients.

Transcription factor 4 promotes increased corneal endothelial cellular migration by altering microtubules in Fuchs endothelial corneal dystrophy

“…Proposed mechanisms for TCF4- CTG repeat expansion toxicity include TCF4 dysregulation, gain-of-function with RNA foci/mis-splicing, repeat-associated non-AUG translation, and somatic instability 23 , 25 – 28 . Several studies have investigated the expression profile of TCF4 in FECD and have obtained differing results 27 – 33 . TCF4- CTG repeat expansion also impacts transcription initiated from nearby 5′ exons, leading to alternative TCF4 protein isoforms, with various levels of transcripts made from alternative promoters 31 .…”