ArticleNucleic acids research2020
Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 2 of them syntheses that pooled it.
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Who cites it
34 citing papers in PubMed, 2 syntheses or guidelines pooled it, 47 citations in OpenAlex.
- Circulating Inflammatory Proteins and Fuchs Endothelial Corneal Dystrophy: A Mendelian Randomization and Bioinformatics-Based Investigation.Translational vision science & technology · 2026Pooled it
- Transcriptomic meta-analysis reveals ERRα-mediated oxidative phosphorylation is downregulated in Fuchs' endothelial corneal dystrophy.PloS one · 2023Pooled it
- Tcf4 CTG Repeat Expansion Induces RNA Toxicity and MBNL-Associated Splicing Dysregulation in a Mouse Model of Fuchs Endothelial Corneal Dystrophy.Investigative ophthalmology & visual science · 2026Article
- Metabolic and redox adaptations of the corneal endothelium: From metabolic plasticity to therapeutic opportunities.Redox biology · 2026Review
- Identification of potential therapeutic targetiScience · 2026Article
- High expression of the underexplored SLC4A11 protein-coding transcript is specific to the corneal endothelium.Scientific reports · 2026Article
- Cross-Cohort Evidence of Editome Dysregulation and Cell Growth-Related IGFBP7 Recoding Driven by ADARB1 in Fuchs Endothelial Corneal Dystrophy.Investigative ophthalmology & visual science · 2026Article
- Integrated Transcriptomics and Experimental Validation Reveal That Ellagic Acid Alleviates Fuchs Endothelial Corneal Dystrophy via PLAU/NF-κB Signaling.Investigative ophthalmology & visual science · 2026Article
- Early Transcriptomic and Pathologic Changes of Col8a2 Mutant Fuchs Endothelial Corneal Dystrophy.Investigative ophthalmology & visual science · 2026Article
- Transcriptome analyses of human corneal endothelial cell lines derived from patients with Fuchs endothelial corneal dystrophy.Scientific reports · 2025Article
- Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy.Scientific reports · 2025Article
- A feasibility of computational drug screening for Fuchs endothelial corneal dystrophy.Scientific reports · 2025Article
- From Genes to Disease: ReassessingInternational journal of molecular sciences · 2025Article
- Heterozygous Tcf4 Deficiency Mitigates Fuchs Endothelial Corneal Dystrophy Progression in a Mouse Model.Investigative ophthalmology & visual science · 2025Article
- The TCF4 Gene Regulates Apoptosis of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy.Investigative ophthalmology & visual science · 2025Article
- How "Omics" Studies Contribute to a Better Understanding of Fuchs' Endothelial Corneal Dystrophy.Current issues in molecular biology · 2025Review
- Transcriptomic analysis implicates the involvement of RBM20 in Fuchs' endothelial corneal dystrophy with TCF4 repeat expansion.PloS one · 2025Article
- Therapeutic potential of omaveloxolone in counteracting muscle atrophy post-denervation: a multi-omics approach.Journal of translational medicine · 2024Article
- Dysregulation of the TCF4 Isoform in Corneal Endothelial Cells of Patients With Fuchs Endothelial Corneal Dystrophy.Investigative ophthalmology & visual science · 2024Article
- Deciphering novel TCF4-driven mechanisms underlying a common triplet repeat expansion-mediated disease.PLoS genetics · 2024Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
How genetic defects trigger the molecular changes that cause late-onset disease is important for understanding disease progression and therapeutic development. Fuchs' endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CTG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at one-two copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because: (i) Affected tissue is routinely removed during surgery; (ii) The expanded CTG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and (iii) The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis. Here, we use RNA sequencing (RNAseq) to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cells. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute magnitude of splicing changes is similar in pre-symptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.