Work

Pathological mechanism in Fuchs endothelial corneal dystrophy and myotonic dystrophy type 1: more than meets the eye

Year: 2025

Type: article

Abstract: Fuchs endothelial corneal dystrophy (FECD) is a heritable disorder distinguished by a progressive degeneration of the corneal endothelium. In its late-onset form, FECD has been associated with a trinucleotide repeat (TNR) expansion (CTG18.1) located in an intronic region of the TCF4 gene, whose frequency is variable among different ancestry groups. Since its discovery, studies investigating CTG18.1-mediated pathogenesis have steadily increased, yet much concerning the unique and tissue-specific clinical features of the disease, as well as its heritable mode of transmission, remain poorly understood. The field of repeat expansion disorders has greatly informed mechanistic understanding of CTG18.1-mediated FECD. In particular, molecular mechanisms underlying myotonic dystrophy type 1, attributed to a CTG expansion in the 3' UTR of the DMPK gene, have considerably informed the FECD field, despite its stark contrast in terms of multisystemic manifestations and variable age at onset. In this work, we critically discuss the non-mutually shared pathogenic parallelisms existing between the pathologies, as well as the unique molecular signatures exhibited by FECD and DM1, speculating on potential research directions for future investigations. Moreover, we discuss the few studies published over the past decade describing the occurrence of FECD in DM1 patients. Here, we debate possible shared molecular signatures that could explain FECD development as a consequence of a non-coding CTG expansion, irrespective of loci (e.g. DMPK or TCF4), and discuss experimental approaches to explain whether these pathologies share toxic mechanisms that arise from these distinct repeat elements.

Source: Progress in Retinal and Eye Research

DOI: 10.1016/j.preteyeres.2025.101418

Authors: Elisa Landi, Derick G. Wansink, Vanessa LaPointe, Hans van Bokhoven, Alice E. Davidson, Mor Dickman