Dysregulation of the TCF4 Isoform in Corneal Endothelial Cells of Patients With Fuchs Endothelial Corneal Dystrophy

Investigative Ophthalmology & Visual Science, Год журнала: 2024, Номер 65(6), С. 27 - 27

Опубликована: Июнь 17, 2024

This study evaluated the dysregulation of TCF4 isoforms and differential exon usage (DEU) in corneal endothelial cells (CECs) Fuchs dystrophy (FECD) with or without trinucleotide repeat (TNR) expansion intron region gene.

Язык: Английский

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Sex-Dependent Variations in Gene Expression in Corneal Endothelial Cells Among Healthy Individuals and Patients With Fuchs Endothelial Corneal Dystrophy

Cornea, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

Purpose: Fuchs endothelial corneal dystrophy (FECD) displays a higher incidence in females than males, yet the underlying mechanism remains unclear. This study aimed to elucidate sex-dependent differential gene expressions cells (CECs) from healthy non-FECD individuals and patients with FECD. Methods: RNA-Seq data CECs of subjects (3 4 females) FECD (5 5 were analyzed identify differentially expressed genes (DEGs) between sexes. We used heatmaps principal component analysis for expression pattern visualization Gene Ontology functional categorization DEGs. Results: Among subjects, we identified 341 DEGs—143 upregulated 198 downregulated—in relative males. For 309 DEGs discovered, 215 94 downregulated compared Heatmaps exhibited hierarchical clustering by sex, whereas delineated distinct male female clusters both cohorts. enrichment linked steroid hormone response, ones cyclin-dependent protein kinase activity. In FECD, associated immune responses peptide binding. Conclusions: To our knowledge, these findings are first reveal patterns The observed variations suggest potential genetic basis sex disparity prevalence. Further investigation is warranted explore associations their implications pathogenesis

Язык: Английский

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How “Omics” Studies Contribute to a Better Understanding of Fuchs’ Endothelial Corneal Dystrophy

Current Issues in Molecular Biology, Год журнала: 2025, Номер 47(3), С. 135 - 135

Опубликована: Фев. 20, 2025

Fuchs’ endothelial corneal dystrophy (FECD) is a progressive eye disease characterized by accelerated loss of cells and the development focal excrescence (guttae) on Descemet’s membrane, resulting in cornea opacity vision deterioration. The FECD assumed to be due interplay between genetic environmental factor risks, causing abnormal extracellular-matrix organization, increased oxidative stress, apoptosis unfolded protein response. However, molecular knowledge limited. genome-wide platforms bioinformatics approaches has enabled us identify numerous loci that are associated with FECD. In this review, we gathered studies (n = 31) sorted them according genomics 9), epigenomics 3), transcriptomics 15), proteomics 3) metabolomics 1) levels characterize progress understanding We also extracted validated differentially expressed/spliced genes proteins identified through comparisons case control groups. addition, highlighted from each omics layer were combined comparison similar study groups original for downstream gene-set enrichment analysis, which provided most significant biological pathways related organization. future, multiomics needed increase sample size statistical power strong candidate functional animal models cell lines better

Язык: Английский

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Transcriptional Profiling of Patients With Fuchs Endothelial Corneal Dystrophy With and Without Trinucleotide Repeat Expansion in TCF4

Cornea, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Purpose: To investigate transcriptomic differences between patients with Fuchs endothelial corneal dystrophy (FECD) and without trinucleotide repeat (TNR) expansion in the transcription factor 4 gene, as genetic basis for FECD lacking TNR remains unclear. Methods: Bulk RNA sequencing was performed on cells from 17 subjects: 10 [4 lengths <50 (RE−) 6 expansions of 50 or more (RE+)] 7 controls. Differential gene expression analysis conducted using DESeq2. Principal component (PCA), correlation matrix analysis, heatmap visualization were used to evaluate patterns. Gene Ontology enrichment differentially expressed genes (DEGs). Results: Analysis identified 509 DEGs (281 upregulated, 228 downregulated) RE− controls, 640 (292 348 RE+ PCA revealed distinct patterns both groups compared Between groups, only identified: ALDH3A1, ENSG00000286252, RNU6-645P, SNORD113-7, RNU6-429P, SNORA16A, COCH, EGFL6, SEMA3E, ENSG00000228463. PCA, demonstrated high similarity overall groups. Conclusions: Contrary expectations, profiles showed remarkable expansion. Further investigation may provide insights into role pathophysiology.

Язык: Английский

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The TCF4 Gene Regulates Apoptosis of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy

Investigative Ophthalmology & Visual Science, Год журнала: 2025, Номер 66(3), С. 16 - 16

Опубликована: Март 6, 2025

Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by excessive extracellular matrix (ECM) accumulation and cell death. CTG trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene represents most significant genetic risk factor. This study aimed to elucidate role of TCF4 FECD pathogenesis through comprehensive proteomic analysis. Corneal cells isolated from patients with harboring were immortalized establish an model (iFECD). CRISPR/Cas9-mediated genome editing was employed generate TCF4-knockout iFECD cells. Whole-cell proteome analysis performed using liquid chromatography-mass spectrometry, followed pathway enrichment differentially expressed proteins (DEPs). The effects deletion on TGF-β-mediated protein aggregation death evaluated Western blot analysis, flow cytometry, aggresome detection assays. Proteomic identified 88 DEPs among 6510 detected proteins. Pathway revealed ECM-associated pathways, oxidative stress responses, cellular motility. attenuated TGF-β-induced Concordantly, demonstrated that suppressed TGF-β2-mediated cleavage caspase-3 poly (ADP-ribose) polymerase. Flow cytometric Annexin V-positive confirmed reduced apoptosis TCF4-deleted following TGF-β2 treatment. Additionally, assays diminished TGF-β2-induced aggregation. demonstrates crucial for pathogenesis, particularly ECM regulation aggregation-induced

Язык: Английский

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Involvement of TGF-β signaling pathway-associated genes in the corneal endothelium of patients with Fuchs endothelial corneal dystrophy

Experimental Eye Research, Год журнала: 2025, Номер unknown, С. 110334 - 110334

Опубликована: Март 1, 2025

Язык: Английский

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Heterozygous Tcf4 Deficiency Mitigates Fuchs Endothelial Corneal Dystrophy Progression in a Mouse Model

Investigative Ophthalmology & Visual Science, Год журнала: 2025, Номер 66(4), С. 19 - 19

Опубликована: Апрель 8, 2025

The purpose of this study was to use Col8a2Q455K/Q455K mice, an established Fuchs endothelial corneal dystrophy (FECD) model, investigate whether heterozygous knockout Tcf4 expression could ameliorate the progression FECD. mice were generated using CRISPR/Cas9-mediated deletion exons 2 and 3. These crossed with obtain Col8a2Q455K/Q455K/Tcf4± mice. Differential gene profiles in cells then examined RNA sequencing. Guttae formation cell density assessed contact specular microscopy. Expression extracellular matrix (ECM) components evaluated by qPCR immunofluorescence analysis. RNA-Seq analysis revealed 1053 differentially expressed genes between significant enrichment ion channel-related pathways downregulation TNF-associated signaling pathways. Contact microscopy 28-week-old demonstrated that guttae significantly lower than (0.71 ± 0.77% vs. 1.87 1.43%, P < 0.001), whereas higher (1819 170 1521 292 cells/mm², 0.001). ECM components-particularly fibronectin type I collagen, which are major constituents guttae-were decreased Heterozygous suppressed FECD phenotype, including loss, mouse model. findings provide vivo support for TCF4 as a potential therapeutic target treatment.

Язык: Английский

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TCF4 expansion–associated loss of FN1 intron retention drives extracellular matrix accumulation in Fuchs endothelial corneal dystrophy

Experimental Eye Research, Год журнала: 2025, Номер unknown, С. 110398 - 110398

Опубликована: Апрель 1, 2025

Язык: Английский

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Targeting the NRF2 pathway: A promising approach for corneal endothelial dysfunction

Current Opinion in Pharmacology, Год журнала: 2024, Номер 74, С. 102429 - 102429

Опубликована: Янв. 2, 2024

Язык: Английский

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Shotgun proteomics identification of proteins expressed in the Descemet’s membrane of patients with Fuchs endothelial corneal dystrophy

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Июнь 27, 2023

Abstract Fuchs endothelial corneal dystrophy (FECD) is a slowly evolving, bilateral disease of the endothelium, characterized by an abnormal accumulation extracellular matrix (ECM) in basement membrane (Descemet’s membrane, DM). This results formation small round excrescences, called guttae, and progressive disappearance cells. In intermediate stage, numerous guttae create significant optical aberrations, late loss function leads to permanent edema. The molecular components have not been fully elucidated. current study, we conducted shotgun proteomics DMs, including obtained from patients with FECD revealed that 32 proteins were expressed only FECD-DMs but DMs control subjects. Subsequent enrichment analyses identified associations multiple ECM-related pathways. Immunostaining flat-mounted confirmed 4 top 5 (hemoglobin α, SRPX2, tenascin-C, hemoglobin γδεβ) non-FECD-DMs. Fibrinogen α was strongly FECD-DMs, weakly We also demonstrated matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) can display situ spatial distribution biomolecules DM, guttae.

Язык: Английский

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