Fuchs Corneal Dystrophy

Eghrari, Allen O.; Riazuddin, Saima; Gottsch, John D.

doi:10.1016/bs.pmbts.2015.04.005

Cited by 72 publications

(77 citation statements)

References 63 publications

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“…Guttae begin centrally and slowly accumulate over time, leading to endothelial cell degeneration due to increased cellular apoptosis and eventually resulting in corneal decompensation. 28 The early-onset form is associated with mutations in the gene coding for collagen type VIII, whereas the late onset, the more common clinical subtype, is linked to numerous different genetic causes. 135 Apart from mutations in TCF8, SLC4A11, LOXHD1, and AGBL1, triplet repeats and single-nucleotide polymorphisms within the TCF4 gene are correlated with the disease; however, they do not completely explain the disease because of the occasional absence of familial Corneal endothelial cell density is the highest in newborns but dramatically decreases when the corneal surface expands.…”

Section: Common Endothelial Diseasesmentioning

confidence: 99%

A review of the evidence for in vivo corneal endothelial regeneration

Bogerd

Dhubhghaill

Koppen

et al. 2018

Survey of Ophthalmology

107

104

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Human corneal endothelium has long been thought to be a nonmitotic cell layer with no endogenous reparative potential. Pathologies that damage endothelial function result in corneal decompensation and, if untreated, blindness. The mainstay of treatment involves partial or complete corneal replacement, amounting to 40% of all corneal transplants performed worldwide. We summarize the case reports describing complications postoperatively in the form of (sub)total graft detachment and those resulting in postoperative bare stroma. Complications during cataract and glaucoma surgeries leading to an uncovered posterior cornea are also included. We discuss the newer treatment strategies that are alternatives for current Descemet membrane endothelial keratoplasty and Descemet stripping automated endothelial keratoplasty, including partial grafts and stripping of the diseased cell layer. In more than half of the cases reviewed, corneal transparency returned despite incomplete or no corneal endothelial cell transplantation. We question the existing paradigm concerning corneal endothelial wound healing in vivo. The data support further clinical study to determine the safety of simple descemethorexis in central endothelial pathologies, such as Fuchs endothelial corneal dystrophy, where presence of healthy peripheral cells may allow successful corneal recompensation without the need for donor cells.

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Section: Common Endothelial Diseasesmentioning

confidence: 99%

A review of the evidence for in vivo corneal endothelial regeneration

Bogerd

Dhubhghaill

Koppen

et al. 2018

Survey of Ophthalmology

107

104

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“…Fuchs Endothelial Corneal Dystrophy (FECD) is a bilateral, heritable degeneration of the corneal endothelium characterized by progressive development of focal excrescences of Descemet’s membrane termed “guttata”, endothelial cell dropout, progressive corneal edema, and loss of vision [7, 8]. Endothelial dystrophies are the most prevalent type of corneal dystrophy, and FECD is the most common of these endothelial dystrophies and is one of the major indications for corneal transplant surgery in the United States (US) and other Western Countries [9–12].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive characterization of DNA methylation changes in Fuchs endothelial corneal dystrophy

et al. 2017

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Transparency of the human cornea is necessary for vision. Fuchs Endothelial Corneal Dystrophy (FECD) is a bilateral, heritable degeneration of the corneal endothelium, and a leading indication for corneal transplantation in developed countries. While the early onset, and rarer, form of FECD has been linked to COL8A2 mutations, the more common, late onset form of FECD has genetic mutations linked to only a minority of cases. Epigenetic modifications that occur in FECD are unknown. Here, we report on and compare the DNA methylation landscape of normal human corneal endothelial (CE) tissue and CE from FECD patients using the Illumina Infinium HumanMethylation450 (HM450) DNA methylation array. We show that DNA methylation profiles are distinct between control and FECD samples. Differentially methylated probes (10,961) were identified in the FECD samples compared with the control samples, with the majority of probes being hypermethylated in the FECD samples. Genes containing differentially methylated sites were disproportionately annotated to ontological categories involving cytoskeletal organization, ion transport, hematopoetic cell differentiation, and cellular metabolism. Our results suggest that altered DNA methylation patterns may contribute to loss of corneal transparency in FECD through a global accumulation of sporadic DNA methylation changes in genes critical to basic CE biological processes.

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“…Control tissues from the eye bank were chosen for analysis that possessed normal endothelial morphology by specular microscopy, were negative for the expanded CUG mutation, and were from donors with ages comparable to our FECD patient cohort ( Figure 2B). Obtaining tissue from Pre_S individuals was possible because of the relatively high prevalence, 3%, of the expanded triplet repeat mutation in TCF4 gene within the general Caucasian population (2,3). Pre_S tissue was identified by the presence of the CUG repeat expansion by genotyping.…”

Section: Resultsmentioning

confidence: 99%

“…Inherited corneal dystrophies can compromise the structure and transparency of the cornea. Late-onset Fuchs' endothelial corneal dystrophy (FECD) is one of the most common genetic disorders, affecting four percent of the population in the United States over the age of forty (2)(3)(4). The corneal endothelium is the inner hexagonal monolayer responsible for maintenance of stromal dehydration and corneal clarity.…”

Section: Introductionmentioning

confidence: 99%

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

Mootha

Corey

Chu

et al. 2020

Preprint

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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 CUG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at 1-2 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; 1) Affected tissue is routinely removed during surgery; 2) The expanded CUG 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 3) 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 cell-specific manner. 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 presymptomatic 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. 3 3 6 6

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Fuchs Corneal Dystrophy

Cited by 72 publications

References 63 publications

A review of the evidence for in vivo corneal endothelial regeneration

A review of the evidence for in vivo corneal endothelial regeneration

Comprehensive characterization of DNA methylation changes in Fuchs endothelial corneal dystrophy

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

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