TCF4-mediated Fuchs endothelial corneal dystrophy : Insights into a common trinucleotide repeat-associated disease

Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved..

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 (CTG18.1) expansion 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.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:81

Enthalten in:

Progress in retinal and eye research - 81(2021) vom: 02. März, Seite 100883

Sprache:

Englisch

Beteiligte Personen:

Fautsch, Michael P [VerfasserIn]
Wieben, Eric D [VerfasserIn]
Baratz, Keith H [VerfasserIn]
Bhattacharyya, Nihar [VerfasserIn]
Sadan, Amanda N [VerfasserIn]
Hafford-Tear, Nathaniel J [VerfasserIn]
Tuft, Stephen J [VerfasserIn]
Davidson, Alice E [VerfasserIn]

Links:

Volltext

Themen:

CTG18.1
FECD
Fuchs endothelial corneal dystrophy
Journal Article
RAN translation
RNA toxicity
Repeat-expansion
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
TCF4 protein, human
Transcription Factor 4
Transcription factor 4
Trinucleotide repeat
Triplet repeat-mediated disease

Anmerkungen:

Date Completed 11.11.2021

Date Revised 11.11.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.preteyeres.2020.100883

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM313114897