Expanded CTG repeat RNA transcribed from the Transcription factor 4 gene (TCF4 CTG repeat RNA)

The expanded CTG repeat RNA transcribed from the Transcription factor 4 (TCF4) gene is the central pathogenic component in the majority of cases of Fuchs' endothelial corneal dystrophy (FECD) (PMID: 20818383). This RNA is produced from a trinucleotide repeat expansion, specifically the CTG18.1 locus located within intron 3 of the TCF4 gene (PMID: 28814544). When transcribed, the expanded CUG repeats form stable secondary structures that aggregate into nuclear RNA foci, which sequester RNA-binding proteins such as Muscleblind-like 1 (MBNL1) (PMID: 25344691). This sequestration leads to a functional loss of these proteins, resulting in a 'spliceopathy' or the mis-splicing of numerous downstream pre-mRNAs essential for corneal endothelial cell health. Therapeutic interventions, such as antisense oligonucleotides (ASOs), are designed to bind to these repeats and trigger the degradation of the toxic RNA or block protein sequestration, thereby restoring normal splicing patterns (PMID: 30308174). Targeting this RNA represents a precision medicine approach to treating the underlying genetic cause of FECD rather than just managing its symptoms.

Other names

TCF4 CUG repeat RNACTG18.1 expanded RNAToxic CUG repeats in TCF4FECD-associated TCF4 RNA expansionExpanded CUG repeat RNA

Antisense oligonucleotides (ASOs) target the expanded CUG repeats within the TCF4 pre-mRNA to induce RNase H-mediated degradation of the toxic transcript or sterically block the repeats to prevent the sequestration of RNA-binding proteins like MBNL1 (PMID: 30308174, PMID: 33434134).