Transcription factor 4 (TCF4) intron 2 expanded CUG trinucleotide repeat (TCF4-CUGexp)

The expanded CUG trinucleotide repeat in intron 2 of the Transcription Factor 4 (TCF4) gene, known as the CTG18.1 locus, is the primary genetic driver of Fuchs' endothelial corneal dystrophy (FECD) (Wieben et al., 2012, PLoS ONE). While normal alleles contain fewer than 40 repeats, pathogenic expansions often exceed 40 and can reach several thousand (Mootha et al., 2014, JAMA Ophthalmology). These expansions are transcribed into sense pre-mRNA that forms toxic nuclear RNA foci, which sequester RNA-binding proteins such as Muscleblind-like 1 (MBNL1) (Du et al., 2015, IOVS). This sequestration leads to a spliceopathy, where the mis-splicing of various downstream transcripts results in the progressive loss of corneal endothelial cells and subsequent corneal edema. Therapeutic strategies, such as those being developed by Tidepool Bio (e.g., TDM-812), utilize antisense oligonucleotides (ASOs) to target and degrade the repeat-containing RNA or block the sequestration of MBNL1, aiming to restore normal splicing and cellular function (Zarouchlioti et al., 2018, AJHG).

Other names

CTG18.1 expansionTCF4 trinucleotide repeat expansionFECD-associated TCF4 repeatTCF4 sense RNA foci

Antisense oligonucleotide-mediated degradation of repeat-containing pre-mRNA via RNase H or steric hindrance to prevent protein sequestration.