TCF4 trinucleotide repeat expansion drives distinct proteomic signatures in Fuchs endothelial corneal dystrophy

Yuasa T, Nakagawa T, Honda T, Nishiuchi G, Sato M, Tokunaga A, Nakahara M, Tourtas T, Schlötzer-Schrehardt U, Kruse F, Padmanabhan P, Chatterjee A, Sathe G, Ghose V, Janakiraman N, Koizumi N, Elchuri SV, Okumura N (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 16

Article Number: 14446

Journal Issue: 1

DOI: 10.1038/s41598-026-43789-x

Abstract

The aims of this study were to use an isogenic cell model system to investigate the proteomic consequences of TCF4 trinucleotide repeat expansion in Fuchs endothelial corneal dystrophy (FECD) and to identify potential molecular pathways contributing to disease pathogenesis. We used our previously established immortalized FECD cells (iFECD) that harbor CTG repeat expansion in TCF4 and CRISPR/Cas9 genome editing to generate an isogenic counterpart (iFECD TCF4ΔCTG) in which the expansion was deleted. Comprehensive proteomic analysis was then performed using tandem mass tag (TMT)-labeled quantitative LC-MS/MS. The resulting data were subjected to differential expression analysis, functional enrichment analysis, and protein-protein interaction network construction to elucidate the molecular impact of the CTG repeat expansion. Deletion of the CTG repeat expansion significantly altered the corneal endothelial proteome, with 90 upregulated and 111 downregulated proteins (|log2 fold change| ≥ 0.5, P-value < 0.05). Functional enrichment analysis revealed that the downregulated proteins were predominantly associated with extracellular matrix organization and cell–substrate adhesion pathways, while the upregulated proteins were enriched in interferon signaling and antigen-processing pathways. The most significantly upregulated proteins included neuropilin-1, Cip1-interacting zinc finger protein, and protein-glutamine gamma-glutamyltransferase 2, while protein phosphatase 1 regulatory subunit 14 C, alpha-crystallin B chain, and 14-3-3 protein sigma showed the greatest downregulation. Our findings demonstrate that TCF4 CTG repeat expansion significantly impacts the corneal endothelial proteome, particularly affecting the extracellular matrix and cell adhesion proteins that likely contribute to guttae formation. These proteomic alterations provide mechanistic insights connecting trinucleotide repeat expansion to endothelial dysfunction and suggest potential therapeutic targets for FECD.

Authors with CRIS profile

Theofilos Tourtas Lehrstuhl für Augenheilkunde Ursula Schlötzer-Schrehardt Department of Ophthalmology Friedrich Kruse Lehrstuhl für Augenheilkunde

Involved external institutions

Doshisha University / 同志社大学 JP Japan (JP) Sankara Nethralaya IN India (IN)

How to cite

APA:

Yuasa, T., Nakagawa, T., Honda, T., Nishiuchi, G., Sato, M., Tokunaga, A.,... Okumura, N. (2026). TCF4 trinucleotide repeat expansion drives distinct proteomic signatures in Fuchs endothelial corneal dystrophy. Scientific Reports, 16(1). https://doi.org/10.1038/s41598-026-43789-x

MLA:

Yuasa, Taichi, et al. "TCF4 trinucleotide repeat expansion drives distinct proteomic signatures in Fuchs endothelial corneal dystrophy." Scientific Reports 16.1 (2026).

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