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Transcription factor 4 and Fuchs’ endothelial corneal dystrophy (FECD) association: Perspectives for novel targeted therapeutics

Eye volume 39, pages 3033–3034 (2025)Cite this article

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Fuchs’ endothelial corneal dystrophy (FECD) is a bilateral female-predominant disease of the innermost layer of the cornea, that occurs at 3–11% of elderly population worldwide [1, 2]. FECD is genetically heterogenic, following the model of autosomal dominant inheritance or sporadic age-related disease [1, 2]. In terms of cytopathology, it is characterised by progressive loss of corneal endothelial cells (CECs) which triggers the formation of an extracellular matrix, called “guttae” and affects visual quality [3]. FECD is classified in two age-related types, the rare early-onset and the most common and severe late-onset which leads to blindness in latter stages [1,2,3]. The variability in clinical presentation and prognosis is driven by the differentiation in prevalence of gene mutations and polymorphisms involved [4,5,6,7]. Therefore, genetic profiling is a prerequisite for a spherical understanding of the molecular pathways that lead to FECD, towards the goal of targeted therapy.

Advances in technological modalities have revealed that mutations in collagen type VIII alpha 2 chain (COL8A2) on chromosome 1, encoding a component of the endothelial basement membrane, are related to early onset. However, the most prominent genetic correlation, is between late-onset FECD and a trinucleotide repeat (TNR) expansion in transcription factor 4 (TCF4) gene [5,6,7,8]. Furthermore, four single nucleotide polymorphisms (SNPs) have been associated with FECD, with TCF4 genetic variant rs613872 to prevail, while rare mutations in solute carrier family 4 sodium-borate cotransporter member 11 (SLC4A11) have been reported, among others [8]. Nevertheless, the key feature in FECD diagnosis is an intronic cytosine-thymine-guanine (CTG) expansion in TCF4 gene on chromosome 18, with specificity that approaches 90% [1, 5,6,7, 9,10,11]. Homozygotes in CTG18.1 expansion are at a 30-fold increased risk to develop FECD compared to controls, underscoring its significant prognostic value [6, 9, 10]. In USA, approximately 70% of FECD patients harbour CTG18.1, indicating the strong penetrance of TCF4 gene regardless its ethnic variability [6, 12]. Numerous studies conclude that the globally accepted cut off for diagnosis is above 40 TNRs [1, 2, 5, 6, 9,10,11,12,13]. Notably, a positive correlation between TNRs’ length and disease severity is consolidated, whilst TNR over 50 is a strong indication for endothelial keratoplasty (EK), a type of partial-thickness corneal transplant technique [14, 15]. Implementation of first line treatment is a cost-effective, symptomatic therapy provided that FECD is diagnosed at an early stage. However, corneal transplantation remains the gold standard for advanced FECD, irrespective of genetic associations [14, 15]. Currently, Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) is considered the EK technique of choice, due to minimal invasiveness, low risk of complications, and effectiveness [14, 15]. Nevertheless, it has limitations regarding to low but significant ratio of graft failure, sight-threatening complications, global shortage of suitable donor tissues, and long visual rehabilitation [12]. Accordingly, future therapies focus on regenerative approaches to delay or even eliminate the need for EK.

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Data analysed during this study are included in this published article. More specific information is available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Angeliki Margoni & Athanasios G. Papavassiliou

  2. First University Department of Respiratory Medicine, ‘Sotiria’ Chest Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Kostas A. Papavassiliou

Authors
  1. Angeliki Margoni
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  2. Kostas A. Papavassiliou
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  3. Athanasios G. Papavassiliou
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Contributions

AM and AGP designed the study. AM and KAP obtained the data. AM prepared the first draft of the manuscript, which was critically reviewed and revised by all authors (AM, KAP, AGP).

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Correspondence to Athanasios G. Papavassiliou.

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Margoni, A., Papavassiliou, K.A. & Papavassiliou, A.G. Transcription factor 4 and Fuchs’ endothelial corneal dystrophy (FECD) association: Perspectives for novel targeted therapeutics. Eye 39, 3033–3034 (2025). https://doi.org/10.1038/s41433-025-04106-4

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