Expanded CTG repeat RNA from the transcription factor 4 gene

The expanded CTG repeat RNA from the transcription factor 4 (TCF4) gene—specifically the non-coding expansion known as CTG18.1—results in formation of pathogenic CUG repeat-containing RNAs. These expanded RNAs form nuclear RNA foci that sequester essential RNA-binding proteins, primarily muscleblind-like 1 (MBNL1), causing widespread disturbance of pre-mRNA splicing in affected cells. This mechanism leads directly to the pathogenesis of Fuchs endothelial corneal dystrophy (FECD) and draws parallels to similar gain-of-function RNA toxicity seen in repeat expansion diseases like myotonic dystrophy type 1. The pathogenic effect is mediated not by changes in TCF4 protein levels but by the toxic action of the mutant RNA on normal cellular RNA splicing machinery, leading to cellular dysfunction and ultimately clinical disease manifestation[1][3][4]. No approved drugs specifically target this RNA; the repeat length and presence of nuclear foci serve as biomarkers for disease state and tissue involvement[1][3][4].

Other names

TCF4-expanded CTG repeat RNATCF4 CTG18.1 repeatTCF4 trinucleotide repeat expansion RNATCF4 CUG RNA foci

Sequestration of RNA-binding proteins (e.g., MBNL1), leading to missplicing; Formation of toxic RNA foci