Transcription factor 4 CTG18.1 trinucleotide repeat expansion (TCF4 CTG18.1 expansion)

The CTG repeat expansion at the TCF4 CTG18.1 locus is a genetic abnormality located within the third intron of the Transcription Factor 4 (TCF4) gene [Wieben et al., 2012; PubMed]. In healthy individuals, this locus typically contains fewer than 40 CTG repeats, but expansions exceeding 40-50 repeats are strongly associated with the development of late-onset Fuchs' endothelial corneal dystrophy (FECD) [Fautsch et al., 2021; NIH]. These expanded repeats are transcribed into toxic CUG-containing RNA, which accumulates as nuclear foci and sequesters essential RNA-binding proteins, most notably Muscleblind-like 1 (MBNL1) [Zarouchlioti et al., 2018; PubMed]. This sequestration leads to widespread alternative splicing defects in corneal endothelial cells, ultimately resulting in cell death and corneal opacity [UniProt]. Therapeutic strategies currently under investigation focus on using antisense oligonucleotides (ASOs) to selectively degrade the expanded RNA or block its interaction with proteins, thereby restoring normal cellular function [Zarouchlioti et al., 2018; PubMed]. Because the expansion is intronic, targeting it offers a way to treat the disease without necessarily disrupting the production of the vital TCF4 protein itself [Fautsch et al., 2021; NIH]. Experimental approaches also include CRISPR/Cas9-mediated excision of the repeat expansion to permanently correct the genetic defect in corneal cells [PubMed]. Clinical management currently relies on corneal transplantation, making these molecular targets highly significant for developing the first pharmacological treatments for FECD [NIH].

Other names

TCF4 CTG repeatCTG18.1 locus expansionFuchs' dystrophy-associated TCF4 repeatCUG repeat RNA

RNase H-mediated degradation of expanded CUG-repeat RNA transcripts to prevent sequestration of RNA-binding proteins like MBNL1 and restore normal splicing.