Secret secretions: the story behind dysregulated extracellular matrixproteins in TCF4 expansion-mediated Fuchs Endothelial Corneal Dystrophy
Final Report Abstract
Fuchs endothelial corneal dystrophy (FECD) is the most common inherited corneal disease and a leading cause of visual impairment and corneal transplantation. As life expectancy increases, the prevalence of this age-related condition is rising, placing a growing burden on healthcare systems. Most individuals with Fuchs endothelial corneal dystrophy (FECD) carry the same genetic risk factor, a non-coding CTG repeat expansion within the TCF4 gene (CTG18.1). However, it is still unclear how this expansion leads to the disease. Studies investigating how the disease-causing genetic changes in FECD modify its clinical characteristics in correlation to the CTG18.1 expansion and studies investigating the histological differences between CTG18.1 expansion positive (Exp+) and CTG 18.1 expansion negative FECD (Exp-) are insufficient. During the Walter Benjamin programme, I investigated the molecular mechanisms behind FECD and the correlation between genotype and its observable corneal characteristics (genotype-phenotype correlation), focusing on differences between affected individuals with (Exp+) or without (Exp-) expansions in CTG18.1. As part of the fellowship, I examined full-thickness cross-sectional corneal tissue and blood-derived gDNA samples from individuals with FECD who underwent corneal transplantation (keratoplasty). In part one, I conducted an explorative search for histopathological differences in the appearance of guttae (disease defining deposits on the inner surface of the cornea) using standard staining (hematoxylin and eosin, periodic acid-Schiff) and light microscopy. CTG18.1 expansion status did not appear to affect histopathological guttae appearance. However, sex and coexisting keratoconus were found to potentially exert influence on guttae appearance, highlighting these covariates as interesting. In part two, I investigated the dysregulation of extracellular matrix (ECM) proteins in genetic data (= transcriptomic data from mRNA) and immunohistochemical observations for expansion positive corneas compared to expansion negative corneas and healthy controls using confocal imaging. Upregulation of the protein fibronectin (FN1) within corneal tissue is a known hallmark of FECD. One of our main findings was that the isoforms and downstream binding partners at the protein level vary in FECD corneal tissues with and without the expansion corroborating our previous transcriptomic findings, highlighting their potential role in disease pathogenesis. My research contributed to an in-depth knowledge about specific pathogenetic pathways in FECD. This can help to identify therapeutic target points and to detect genetic and molecular biomarkers to develop and assess the efficacy of potential gene-directed therapeutics to improve vision and quality of life of patients with FECD.
Publications
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FECD: a pilot study to explore the diagnostic value of histopathological images for genotype prediction. British Association for Ophthalmic Pathology Annual Meeting (BAOP). 03/2024. London, England
Kladny A.M.S., Bhattacharyya N., Davidson A. & Thaung C.
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From genotype to phenotype: exploring the histopathological differences of fuchs endothelial corneal dystrophy genetic subtypes. Annual meeting of the DOG. 10/2024. Berlin, Germany
Kladny A.M.S., Bhattacharyya N., Tuft S., Thaung C. & Davidson A.
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From genotype to phenotype: Exploring the histopathological differences of Fuchs endothelial corneal dystrophy genetic subtypes. Annual UCL IoO Early Career Researchers (ECR) Symposium. 06/2024. London, England
Kladny A.M.S., Bhattacharyya N., Davidson A. & Thaung C.
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Characterizing the extracellular landscape of Fuchs endothelial corneal dystrophy. ARVO 5/2025. Utah, USA
Kladny, A.M.S., Bhattacharyya, N., Zarouchlioti, C., Muthusamy, K., Thaung, C., Tuft, S. & Davidson, A.
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Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity. JAMA Ophthalmology, 143(4), 338.
Liu, Siyin; Sadan, Amanda N.; Bhattacharyya, Nihar; Zarouchlioti, Christina; Szabo, Anita; Abreu Costa, Marcos; Hafford-Tear, Nathaniel J.; Kladny, Anne-Marie S.; Dudakova, Lubica; Ciosi, Marc; Moghul, Ismail; Wilkins, Mark R.; Allan, Bruce; Skalicka, Pavlina; Hardcastle, Alison J.; Pontikos, Nikolas; Bunce, Catey; Monckton, Darren G.; Muthusamy, Kirithika ... & Davidson, Alice E.
