Transcription factor 4 (TCF4) CTG18.1 expanded CUG-repeat RNA (TCF4 CUG-repeat RNA)

The expanded TCF4 CTG18.1 CUG-repeat RNA is a pathogenic transcript resulting from a trinucleotide repeat expansion within the TCF4 gene, specifically at the intronic CTG18.1 locus (Wieben et al., 2012, PLoS ONE). This expansion, typically exceeding 40-50 repeats, is the most significant genetic risk factor for Fuchs' endothelial corneal dystrophy (FECD), a leading cause of corneal transplant surgery (Vithana et al., 2013, JAMA Ophthalmology). The resulting CUG-repeat RNA molecules accumulate in the nuclei of corneal endothelial cells, forming toxic RNA foci that are a hallmark of the disease (Zarouchlioti et al., 2018, American Journal of Human Genetics). These foci sequester essential RNA-binding proteins, most notably Muscleblind-like 1 (MBNL1), leading to widespread alternative splicing defects and subsequent cellular dysfunction (Mootha et al., 2015, Investigative Ophthalmology & Visual Science). Therapeutic interventions currently under investigation aim to target this toxic RNA using antisense oligonucleotides (ASOs) or small molecules to either induce its degradation or block its interaction with sequestered proteins (Hu et al., 2018, Molecular Therapy). Successfully reducing the burden of these RNA foci is expected to restore normal splicing patterns and preserve the function and density of corneal endothelial cells.

Other names

TCF4 CTG18.1 expansionExpanded CUG RNA in TCF4FECD-associated TCF4 RNACTG18.1 trinucleotide repeat RNA

Degradation of toxic expanded RNA via RNase H-mediated cleavage or steric hindrance to prevent the sequestration of RNA-binding proteins like MBNL1.