Fautsch, MP;
Wieben, ED;
Baratz, KH;
Bhattacharyya, N;
Sadan, AN;
Hafford-Tear, NJ;
Tuft, SJ;
(2020)
TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat associated disease.
Progress in Retinal and Eye Research
, Article 100883. 10.1016/j.preteyeres.2020.100883.
(In press).
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Abstract
Fuchs endothelial corneal dystrophy (FECD) is a common cause for heritable visual loss in the elderly. Since the first description of an association between FECD and common polymorphisms situated within the transcription factor 4 (TCF4) gene, genetic and molecular studies have implicated an intronic CTG trinucleotide repeat expansion (CTG18.1) as a causal variant in the majority of FECD patients. To date, several non-mutually exclusive mechanisms have been proposed that drive and/or exacerbate the onset of disease. These mechanisms include (i) TCF4 dysregulation; (ii) toxic gain-of-function from TCF4 repeat-containing RNA; (iii) toxic gain-of-function from repeat-associated non-AUG dependent (RAN) translation; and (iv) somatic instability of CTG18.1. However, the relative contribution of these proposed mechanisms in disease pathogenesis is currently unknown. In this review, we summarise research implicating the repeat expansion in disease pathogenesis, define the phenotype-genotype correlations between FECD and CTG18.1 expansion, and provide an update on research tools that are available to study FECD as a trinucleotide repeat expansion disease. Furthermore, ongoing international research efforts to develop novel CTG18.1 expansion-mediated FECD therapeutics are highlighted and we provide a forward-thinking perspective on key unanswered questions that remain in the field.
| Type: | Article |
|---|---|
| Title: | TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat associated disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.preteyeres.2020.100883 |
| Publisher version: | https://doi.org/10.1016/j.preteyeres.2020.100883 |
| Language: | English |
| Additional information: | This is an Open Access article published under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | CTG18.1, FECD, Fuchs endothelial corneal dystrophy, RAN translation, RNA toxicity, Repeat-expansion, Transcription factor 4, Trinucleotide repeat, Triplet repeat-mediated disease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107482 |
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