TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease. (March 2021)

• Record Type: Journal Article
• Authors: Fautsch, Michael P.; Wieben, Eric D.; Baratz, Keith H.; Bhattacharyya, Nihar; Sadan, Amanda N.; Hafford-Tear, Nathaniel J.; Tuft, Stephen J.; Davidson, Alice E.
• Is Part Of: Progress in retinal and eye research. Volume 81(2021)
• Publication Date: 2021-03
• Subjects: Fuchs endothelial corneal dystrophy -- Repeat-expansion -- Transcription factor 4 -- Triplet repeat-mediated disease -- Trinucleotide repeat -- FECD -- CTG18.1 -- RNA toxicity -- RAN translation; Retina -- Periodicals; Retina -- Research -- Methodology -- Periodicals; Eye -- Diseases -- Periodicals; Eye -- Periodicals; Eye Diseases -- Periodicals; Retina -- Periodicals; Rétine -- Périodiques; Rétine -- Recherche -- Méthodologie -- Périodiques; 617.7005
• DOI: 10.1016/j.preteyeres.2020.100883
• Languages: English
• ISSNs: 1350-9462

Abstract

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 (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. Highlights: FECD is a common, age-related corneal dystrophy. The majority of cases are associated with expansion of a CTG repeat (CTG18.1). FECD is the most common trinucleotide repeat expansion disease in humans. Evidence supports multiple molecular mechanisms underlying the pathophysiology. Novel CTG18.1-targeted therapeutics are in development.