Materiały źródłowe

• #1 REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6571125/

  Fuchs endothelial corneal dystrophy (FECD) is the most prominent reason for corneal-endothelial transplantations across the globe. The disease pathophysiology manifests through a combination of various genetic and non-heritable factors. This review provides a comprehensive list of known genetic players that cause FECD, and discusses the prominent pathological features that participate in disease progression, such as channel dysfunction, abnormal extracellular matrix deposition, RNA toxicity, oxidative stress, and apoptosis. […] Although the primary cause of this disease is unknown, clinical samples exhibit significant endothelial cell loss, edematous cornea, and a thickening in the endothelial basement Descemets membrane. These manifestations disturb corneal deturgescence, resulting in suboptimal endothelial membrane function.

• #2 Fuchs Endothelial Dystrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545248/

  Fuchs endothelial dystrophy (FED) is a progressive, bilateral corneal disorder that leads to corneal endothelial dysfunction, fluid retention, and vision impairment. […] The pathophysiology involves progressive loss of corneal endothelial cells, leading to impaired fluid regulation, Descemet membrane thickening, and guttata formation, which contribute to corneal edema and vision deterioration. […] The pathophysiology of FED involves several proposed mechanisms, including channelopathies, oxidative stress, apoptosis, and epithelial-mesenchymal transition (EMT). Despite multiple hypotheses, the precise underlying mechanisms remain unclear. A key contributor to FED development is channelopathy in the corneal endothelium, characterized by ion channel dysfunction due to genetic mutations. For example, mutations in SLC4A11 disrupt normal endothelial function.

• #3 Fuchs’ Endothelial Dystrophy – EyeWiki

  https://eyewiki.org/Fuchs%E2%80%99_Endothelial_Dystrophy

  Fuchs endothelial dystrophy is a non-inflammatory, sporadic or autosomal dominant, dystrophy involving the endothelial layer of the cornea. […] The damage to the cornea in Fuchs endothelial dystrophy can be so severe as to cause corneal blindness. […] Over the course of decades, the cornea develops guttae and increases in thickness, causing glare, halos, and reduced visual acuity. […] Fuchs dystrophy is often inherited in an autosomal dominant manner. […] The genetics of classic, late-onset Fuchs’ dystrophy is complex and multifactorial. […] The strongest association identified has been with expansion of the CTG18.1 trinucleotide repeat in TCF4. […] In large cohorts of people with Fuchs’ dystrophy, approximately two out of three people harbor this genetic variant, an expanded trinucleotide repeat.

• #4 Molecular Vision: REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  http://www.molvis.org/molvis/v25/295/

  Fuchs endothelial corneal dystrophy (FECD) is the most prominent reason for corneal-endothelial transplantations across the globe. The disease pathophysiology manifests through a combination of various genetic and non-heritable factors. This review provides a comprehensive list of known genetic players that cause FECD, and discusses the prominent pathological features that participate in disease progression, such as channel dysfunction, abnormal extracellular matrix deposition, RNA toxicity, oxidative stress, and apoptosis. […] Although the primary cause of this disease is unknown, clinical samples exhibit significant endothelial cell loss, edematous cornea, and a thickening in the endothelial basement Descemets membrane. These manifestations disturb corneal deturgescence, resulting in suboptimal endothelial membrane function.

• #5 REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6571125/

  FECD is a multigenic disorder that imparts complex pathophysiology. These diverse genetic factors either develop sporadically or have a familial predisposition. […] Thus far, researchers have identified eight different genetic loci that cosegregate with FECD, either through linkage analysis or a GWAS. […] The primary function of the cornea is to maintain deturgescence, which is corneal hydration, thickness, and transparency. The corneal endothelium plays a significant role in carrying out this function; therefore, deterioration of the corneal endothelium can cause the characteristic corneal edema seen in FECD. […] A dysfunctional pump and barrier system can disturb the corneal deturgescence, and cause edema. FECD is a case of channelopathy where disease-causing mutations accumulate secondary outcomes where ion channels, such as solute carrier family 4 member 11 (SLC4A11), Na+, K+ transporting ATPase (Na+/K+ ATPase), aquaporin 1 (AQP-1), and monocarboxylate transporters (MCTs), either are dysfunctional or are less populated on the cell membrane.

• #6 Molecular Vision: REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  http://www.molvis.org/molvis/v25/295/

  This review discusses various risk factors, and their pathological contribution associated with the progression of FECD. The review also focuses on recent advances in surgical and noninvasive techniques developed to restore vision deprived due to the disease. […] FECD is a multigenic disorder that imparts complex pathophysiology. These diverse genetic factors either develop sporadically or have a familial predisposition. […] Thus far, researchers have identified eight different genetic loci that cosegregate with FECD, either through linkage analysis or a GWAS. […] The primary function of the cornea is to maintain deturgescence, which is corneal hydration, thickness, and transparency. The corneal endothelium plays a significant role in carrying out this function; therefore, deterioration of the corneal endothelium can cause the characteristic corneal edema seen in FECD.

• #7 Fuchs dystrophy – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/fuchs-dystrophy/symptoms-causes/syc-20352727

  Fuchs dystrophy is a condition in which fluid builds up in the clear tissue at the front of the eye, called the cornea. This causes your cornea to swell and thicken, leading to glare, blurred or cloudy vision, and eye discomfort. […] The cells lining the inside of the cornea are called endothelial cells. Those cells help maintain a healthy balance of fluid within the cornea and keep the cornea from swelling. In Fuchs dystrophy, the endothelial cells slowly die or do not work well, causing fluid buildup within the cornea. The fluid buildup, called edema, causes thickening of the cornea and blurred vision. […] Fuchs dystrophy tends to run in families. The genetic basis of the disease is complex. Family members can be affected to different degrees or not at all.

• #8 Cornea Louisville | Fuchs Dystrophy Louisville | Bennett & Bloom

  https://www.eyecenters.com/cornea-and-conjunctiva-louisville/fuchs-endothelial-dystrophy-fed/

  Fuchs Endothelial Dystrophy (FED) is a genetic disease of the cornea. […] The inner layer of the cornea is lined by tissue, Descemets membrane (DM), that is as thin as Saran wrap. This membrane has special endothelial cells that live on it whose job it is to keep the cornea clear. In FED, the DM becomes irregular and distorted (guttata deposition) while the endothelial cells die off and cant do their job. Over time, the cornea becomes swollen and foggy. […] The cornea and other parts of the eye have no blood flow but need oxygen and nutrients like any other part of the body. […] Because the endothelial cells in Fuchs are dying off, they cant do their job so fluid builds, causing the cornea to swell and become hazy. […] Having your eyes open while awake helps some of the excess corneal fluid escape via evaporation. While closing your eyelids all night long, the endothelial cells get no such help and can get behind by morning. The cornea, therefore, is swollen and hazy when you wake up, causing your vision to be blurry. […] When enough cells die off, evaporation is not enough to clear the cornea by itself, so during full decompensation, the cornea stays severely cloudy all day.

• #9 Fuchs Endothelial Dystrophy: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1193591-overview

  Fuchs endothelial dystrophy (FED) is characterized by an asymmetrical, bilateral, slowly progressive edema of the cornea in elderly patients. When inherited, the transmission is autosomal dominant. Corneal endothelium is a monolayer of cells that acts as the major pump to deturgesce the cornea and ensures clarity. The normal attrition rate of endothelial cells is 0.6% per year; the rate is accelerated in Fuchs endothelial dystrophy. The root cause of the condition is a slowly progressive formation of guttate lesions between the corneal endothelium and the Descemet membrane. […] In Fuchs dystrophy, the basic lesion appears to be cornea guttata. Upon ultrastructural examination, this newly deposited abnormal portion of Descemet membrane consists of bundles and sheets of widely spaced, banded collagen and multiple laminations of basement membrane material. Endothelial cells may produce these wartlike, mushroom-shaped or anvil-shaped excrescences. Guttate excrescences in the peripheral cornea are of no consequence. However, their strong presence in the center of the cornea foreshadows trouble in the coming years. The increasing cornea guttata thins and progressively destroys the endothelial cells. The remaining cells enlarge and cover the gaps.

• #10 Fuchs Endothelial Corneal Dystrophy: From One Medical Student to Another

  https://eyerounds.org/tutorials/fuchs-endothelial-corneal-dystrophy-med-student/index.htm

  Fuchs Endothelial Corneal Dystrophy (FECD) is a corneal dystrophy affecting primarily the deepest layer of the cornea, known as the corneal endothelium. […] Though it is a normal part of aging, endothelial cell death is severely exacerbated in FECD. […] Since corneal endothelial cells do not regenerate, neighboring cells must migrate and fill gaps in this cell layer. […] This leads to a loss in barrier and pump function, and disrupted regulation of proper corneal hydration. […] As endothelial cells die, remaining cells migrate, grow, and lose their characteristic hexagonal shape in order to fill in these gaps. […] This behavior results in the characteristic polymegathism and pleomorphism, respectively, that is observed on specular microscopy in patients with FECD. […] Additionally, FECD is a disease characterized by abnormal extracellular matrix deposition, which leads to the buildup of collagen excrescences, known as guttae, that accumulate, initially centrally, on the endothelium and can be detected on slit lamp examination.

• #11 What is Fuchs Dystrophy? | Harvard Medical School Department of Ophthalmology

  https://eye.hms.harvard.edu/book/what-fuchs-dystrophy

  Fuchs dystrophy is an age-related progressive corneal disorder that affects both eyes and occurs when endothelial cells gradually die, leading to deposition of drop-like deposits (guttae) and corneal edema. […] Although Fuchs has a genetic basis, most commonly due to TCF4 gene mutation, it does not cause symptoms or affect vision until middle age or later in life. […] Fuchs dystrophy has 4 stages: […] Stage 1: Early findings of central non-confluent guttae. […] Stage 2: The guttae become confluent, causing more glare and loss of contrast sensitivity. […] Stage 3: There is onset of corneal edema leading to cloudy vision, most commonly in the morning, that clears up during the day. […] Stage 4: The edema becomes more severe, causing blurry or hazy vision to persist throughout the day.

• #12 Molecular Vision: REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  http://www.molvis.org/molvis/v25/295/

  A dysfunctional pump and barrier system can disturb the corneal deturgescence, and cause edema. FECD is a case of channelopathy where disease-causing mutations accumulate secondary outcomes where ion channels, such as solute carrier family 4 member 11 (SLC4A11), Na+, K+ transporting ATPase (Na+/K+ ATPase), aquaporin 1 (AQP-1), and monocarboxylate transporters (MCTs), either are dysfunctional or are less populated on the cell membrane. […] The initial pathogenic indication of FECD involves thick deposition of fibronectin, followed by deregulated expression of laminin and type IV collagen in the posterior face of Descemets membrane in advanced stages. […] The pathological outcomes of repeat-expansion diseases can be explained by two distinct mechanisms: the toxicity of RNA repeats and the toxicity of repeat-associated non-ATG (RAN) translation, or a combination of the two.

• #13 Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy | Eye and Vision | Full Text

  https://eandv.biomedcentral.com/articles/10.1186/s40662-021-00246-2

  Autophagy is a cellular process featuring ER stress and oxidative stress. Forming autophagosomes and combining them with lysosomes, autophagosomes phagocytose the resulting substance and the organelles in the cell. Autophagy plays an important protective role in cells. […] The up-regulation of EMT-related genes ZEB1 and SNAI1 by TGF- in CECs in FECD patients was associated with the deposition of ECM proteins. […] Wieben et al. were the first to report that the corneal endothelium from FECD patients harbored a unique signature of mis-splicing events caused by CTG TNR expansion in the TCF4 gene. […] A recent study found that SLC4A11 is a cell adhesion molecule, mediating CECs adhesion to DM. […] This review reveals that our understanding of the pathogenesis of FECD and the development of molecular genetics is becoming more profound. The gene mutation site has been established and the molecular mechanisms are becoming clearer. However, many questions regarding the pathogenesis remain elusive. Overall, the data from the studies included here illuminate the molecular mechanisms associated with FECD and may help to optimize various therapeutic approaches.

• #14 REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6571125/

  The initial pathogenic indication of FECD involves thick deposition of fibronectin, followed by deregulated expression of laminin and type IV collagen in the posterior face of Descemets membrane in advanced stages. […] The pathological outcomes of repeat-expansion diseases can be explained by two distinct mechanisms: the toxicity of RNA repeats and the toxicity of repeat-associated non-ATG (RAN) translation, or a combination of the two. […] FECD is a result of heightened oxidative stress in decompensated corneal endothelial cells with an inefficient mitochondrial system. […] Various genetic and environmental stressors accumulate spontaneous mutations over a period. Depending on the site of mutagenesis, they can lead to cell toxicity (aberrant protein folding), nuclear toxicity (RNA foci formation), or deregulation of essential genes involved in maintaining crucial corneal endothelial functions, such as hydration, fluid flux, mitochondria-mediated ATP generation, DNA repair, and antioxidant production.

• #15 Molecular Vision: REVIEW: Current understanding of the pathogenesis of Fuchs’ endothelial corneal dystrophy

  http://www.molvis.org/molvis/v25/295/

  Corneal endothelial cells are metabolically demanding due to the constant flux of ions and fluids; thus, these cells are the most populated with mitochondria in comparison to all other ocular tissues. FECD is a result of heightened oxidative stress in decompensated corneal endothelial cells with an inefficient mitochondrial system. […] To summarize, various genetic and environmental stressors accumulate spontaneous mutations over a period. Depending on the site of mutagenesis, they can lead to cell toxicity (aberrant protein folding), nuclear toxicity (RNA foci formation), or deregulation of essential genes involved in maintaining crucial corneal endothelial functions, such as hydration, fluid flux, mitochondria-mediated ATP generation, DNA repair, and antioxidant production. One or several of these events can co-occur, to bring out the pathophysiological etiology of FECD.

• #16 Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy | Eye and Vision | Full Text

  https://eandv.biomedcentral.com/articles/10.1186/s40662-021-00246-2

  The corneal endothelium is particularly vulnerable to oxidative stress because it is exposed to light and vigorous metabolic activity caused by a high oxygen demand. Increased nitrotyrosine, a by-product of ROS, suggests that oxidative damage indeed occurs in FECD. […] Mitochondria, found in eukaryotic cells, are organelles covered by two membranes. They are the main site of ATP production within the electron transport chain. In addition to energy supply, mitochondria participate in other cell processes such as regulating calcium levels and apoptosis. […] Apoptosis, the spontaneous and orderly death of genetically controlled cells, is characterized by cell shrinkage, membrane blebbing, chromatin condensation and DNA fragmentation. Apoptosis is considered to be an important mechanism of FECD.

• #17 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Due to its localization and function, the cornea is regularly exposed to sunlight and atmospheric oxygen, mainly dioxygen, which produce reactive oxygen species (ROS). Therefore, corneal cells are particularly susceptible to oxidative stress. […] Keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD) are multifactorial diseases of the cornea, in which pathogenesis is not fully understood. However, increased levels of oxidative stress markers detected in these disorders indicate that oxidative stress may play an important role in their development and progression. […] A growing body of evidence indicates the role of oxidative stress in the development of KC. […] Although autosomal dominant pattern of inheritance in FECD was reported, the precise mode of perpetuation for most cases of the disease remains unknown. FECD is considered as a multifactorial disease, in which genetic, as well as environmental factors, play a role in its development.

• #18 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Results of several studies indicate an association between FECD and oxidative stress. FECD corneas exhibited an accumulation of ROS and RNS products, which were not detected in normal human corneas. […] An aberrant expression of many proteins, including antioxidant enzymes, was reported in FECD endothelial cells. […] Increased oxidative stress in FECD cornea may contribute to endothelial oxidative DNA damage, morphological modification and apoptosis. […] Despite many extensive studies, the pathogenesis of KC and FECD are poorly understood, which is probably underlined by the complexity of these diseases. The role of oxidative stress in both diseases needs further investigation.

• #19 Marshall Digital Scholar

  https://mds.marshall.edu/sm_ophthalmology/5/

  Fuchs endothelial corneal dystrophy (FECD) is a progressive, blinding disease characterized by corneal endothelial (CE) cell apoptosis. […] In this study, we observed a decrease in the antioxidant response element-driven antioxidants in FECD corneal endothelium. […] Importantly, we detected significantly higher levels of oxidative DNA damage and apoptosis in FECD endothelium compared with normal controls and pseudophakic bullous keratopathy (iatrogenic CE cell loss) specimens. […] A marker of oxidative DNA damage, 8-hydroxy-2-deoxyguanosine, colocalized to mitochondria, indicating that the mitochondrial genome is the specific target of oxidative stress in FECD. […] Together, these data suggest that suboptimal nuclear factor erythroid 2-related factor 2-regulated defenses may account for oxidant-antioxidant imbalance in FECD, which in turn leads to oxidative DNA damage and apoptosis. […] This study provides evidence that oxidative stress plays a key role in FECD pathogenesis.

• #20

  https://omim.org/entry/136800

  Azizi et al. (2011) concluded that p53 plays a critical role in complex mechanisms regulating oxidative stress-induced apoptosis in FECD. […] The authors suggested that the underlying pathogenesis of FECD and PPCD2 may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest-derived corneal endothelial cell. […] Jun et al. (2012) concluded that the Q455K mutation in COL8A2 causes FECD through a mechanism involving the UPR and UPR-associated apoptosis. […] Meng et al. (2013) suggested that altered autophagy plays a role in FECD.

• #21 Fuchs Endothelial Dystrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545248/

  Oxidative stress is another significant pathogenetic factor. The cornea is continuously exposed to UV light, generating ROS that damages both mitochondrial and nuclear DNA. This oxidative damage triggers endothelial cell apoptosis, contributing to progressive cell loss. […] The accumulation of oxidative DNA damage around guttata disrupts mitochondrial function, leading to ongoing endothelial loss and ocular tissue degeneration. […] In FED, endothelial cells undergo apoptosis and lose their pump function, leading to excessive hydration of the corneal stroma and epithelium. […] The pathophysiology of FED involves endothelial cell loss, oxidative stress, and genetic susceptibility. […] Genetic susceptibility plays a major role in FED, particularly TCF4 gene trinucleotide repeat expansions, which are identified in nearly 70% of individuals with late-onset disease, making it a strong genetic marker.

• #22 Fuchs Endothelial Dystrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545248/

  The disease advances gradually, leading to significant endothelial cell loss, impaired corneal deturgescence, and bilateral corneal edema affecting the stroma or epithelium. […] In FED, degenerating endothelial cells produce hyaline excrescences known as guttata, which accumulate on the Descemet membrane and correlate with its thickening. These excrescences are visible both histologically and clinically. […] The pathophysiology of FED involves several proposed mechanisms, including channelopathies, oxidative stress, apoptosis, and epithelial-mesenchymal transition (EMT).

• #23 MicroRNA of Epithelial to Mesenchymal Transition in Fuchs’ Endothelial Corneal Dystrophy

  https://www.mdpi.com/2073-4425/13/10/1711

  An excessive expression of genes that bring on EMT, such as ZEB1 and SNAIL1, was proven in FECD corneal endothelial cells. […] The overexpression of these genes was suggested as the basis of elevated susceptibility of FECD corneal endothelial cells to TGF-β. […] The impaired EMT was proposed as a common mechanism in corneal endothelial disorders. […] MiR-29 is one of the three miRNAs of the same family that are the most downregulated mature miRNAs in FECD endothelium. […] The members of the miR-29 family play an important role in the regulation of ECM turnover and fibrotic conditions of different organs and tissues, including the eye. […] The miRNAs from the miR-29 family are the main regulators of the ECM.

• #24 Cataract surgery and Fuchs’ dystrophy | Mallias | Ophthalmology Journal

  https://journals.viamedica.pl/ophthalmology_journal/article/view/OJ.2017.0010/42443

  Fuchs endothelial dystrophy is a non-inflammatory dystrophy involving the endothelial layer of the cornea. […] The pathogenesis of the disease is unclear. Some possible factors may be sex hormones, inflammation, and endothelial cell apoptosis. […] Fuchs dystrophy is often inherited in an autosomal dominant manner. This means that there is a 50% chance for a person to develop the disease if one of the parents has it. Consequently, there is no way of preventing the disease and its progress.

• #25 Fuchs endothelial corneal dystrophy: current perspectives on diagnostic pathology and genetics—Bowman Club Lecture | BMJ Open Ophthalmology

  https://bmjophth.bmj.com/content/7/1/e001103

  Current evidence shows that early-onset FECD is attributed to missense mutations in the extracellular matrix encoding gene COL8A2, while late-onset FECD is genetically heterogeneous. However, a significant majority of the late-onset cases have a shared underlying genetic cause of disease: expansion of a triplet repeat element (termed CTG18.1) situated within an intronic region of the transcription factor encoding gene TCF4. […] Given the majority of FECD cases have CTG18.1 expansions, researchers are now focused on determining how expansion of this non-coding element causes FECD. This knowledge will aid the effective design and development of therapeutic interventions. Currently, at least four non-mutually exclusive mechanisms have been proposed. These include (1) dysregulated expression of a subset of TCF4 transcripts, (2) a toxic accumulation of RNA transcripts transcribed from CTG18.1 expanded alleles and/or (3) non-ATG-dependent translation of repetitive RNA transcripts into toxic repeat peptides and/or (4) age and tissue-specific mechanisms of DNA repeat instability within CECs as covered in a recent review.

• #26 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240919/Study-uncovers-mechanisms-behind-Fuchs-Endothelial-Corneal-Dystrophy.aspx

  Important insights into the mechanisms behind Fuchs Endothelial Corneal Dystrophy (FECD), a common cause of age-related visual loss, have been revealed in a new study led by UCL researchers. […] The research, led by a team in Dr Alice Davidson’s Inherited Corneal Disease Lab at UCL Institute of Ophthalmology, has revealed how FECD progresses at a molecular level, and highlights the importance of understanding genetic instability when cells have high frequency of mutations in developing new treatments for FECD and diseases caused by similar genetic mutations, such as Huntington’s disease and other neurological and neuromuscular diseases. […] A key factor in developing FECD is the expansion of a specific DNA sequence within the TCF4 gene, called CTG18.1. This genetic change, known as a short tandem repeat expansion, has been identified as the most common risk factor for FECD across all studied populations. […] Researchers are now focused on a new series of experiments to understand how this mechanism plays out throughout human development to better understand when may be the most effective time to therapeutically intervene.

• #27 Fuchs endothelial corneal dystrophy: current perspectives on diagnostic pathology and genetics—Bowman Club Lecture | BMJ Open Ophthalmology

  https://bmjophth.bmj.com/content/7/1/e001103

  Although FECD is now known to have a strong genetic component, this was not initially recognised. Inherited cases were thought to be a small proportion of total cases. […] In 2010, a comparatively small-scale genome wide association study provided compelling evidence for FECD being surprisingly genetically homogenous. The study identified a common polymorphism, located within an intronic region of the TCF4 gene on Chromosome 18, that conferred up to a 30-fold increased risk for FECD. […] Two years later, the functional variant underlying this signal of association was identified: expansion of a non-coding intronic triplet repeat element (termed CTG18.1) within TCF4. CTG18.1 repeat length is now well established to be expanded in the majority of FECD cases. […] A slightly later study of three related patients with early-onset FECD and the same COL8A2 mutation suggests that the thickness of Descemet membrane and the clinical severity of the disease (loss of endothelium and resultant oedema) are correlated. The authors postulate that massively thickened Descemet membrane impairs endothelial nourishment from the stroma, hastening cell loss. […] It seems plausible that disease-associated COL8A2 missense mutations could induce conformational shifts in COL8A2 structure that underlie the abnormal distribution of both COL8A2 and COL8A1 in Descemet membrane, given that they form a heterodimer.

• #28

  https://www.omim.org/entry/613267

  Mootha et al. (2015) concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD with CTG18.1 triplet repeat expansion, mediated by CUG-repeat RNA foci. […] Du et al. (2015) concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 (DM1; 160900). […] In a study of 122 white index cases of FECD, Soliman et al. (2015) found that 85 (69.7%) harbored the TCF4 triplet repeat expansion.

• #29

  https://link.springer.com/article/10.1007/s00018-023-04714-x

  Late-onset Fuchs endothelial corneal dystrophy (FECD) is a disease affecting the corneal endothelium (CE), associated with a cytosine-thymine-guanine repeat expansion at the CTG18.1 locus in the transcription factor 4 (TCF4) gene. […] The most revealing DNA methylation findings were analyzed by gene expression and protein analysis. 3488 CpGs had significantly altered methylation pattern in FECD though no substantial changes were found in TCF4. […] Thus, tissue-specific genome-wide and gene-specific methylation changes associated with altered gene expression were discovered in FECD. TCF4 pathological methylation in FECD because of CTG18.1 expansion was ruled out. […] One of the proposed pathogenic mechanisms in FECD is the development of tissue-specific RNA nuclear foci formed from the expanded TCF4 repeat tract.

• #30 Ultraviolet Light Exposure Identified as Factor Linked to Eye Disease Fuchs’ Endothelial Corneal Dystrophy – FOCUS

  https://focus.masseyeandear.org/ultraviolet-light-exposure-identified-as-factor-linked-to-eye-disease-fuchs-endothelial-corneal-dystrophy/

  Nowe badania dostarczają wyjaśnienia, dlaczego ta choroba oczu występuje w centralnej części rogówki i jest znacznie częstsza u kobiet. […] Badacze z Mass. Eye and Ear zidentyfikowali możliwy mechanizm, który może wyjaśnić, dlaczego stan ten dotyka tylko niektóre części oka i jest znacznie częstszy u kobiet. […] Stwierdzili, że ekspozycja na światło ultrafioletowe A (UVA) uruchamia reakcję enzymatyczną, która powoduje uszkodzenia DNA obserwowane u pacjentów z FECD. […] Ta reakcja była znacznie bardziej wyraźna u kobiet, ponieważ jest napędzana przez aktywację CYP1B1, enzymu, który przekształca estrogen w metabolity powodujące uszkodzenia DNA. […] Badania wykazały, że kobiety są bardziej dotknięte FECD niż mężczyźni i są bardziej skłonne do operacji. […] Odkryli nową ścieżkę, w której światło UVA powoduje zwiększoną ekspresję enzymu CYP1B1, który uruchamia szlak metabolitów estrogenu, co ostatecznie prowadzi do uszkodzenia DNA. […] To jest mechanizm, który wyjaśnia to, co widzieliśmy u naszych pacjentów.

• #31 Ultraviolet Light Exposure Identified as Factor Linked to Eye Disease Fuchs Endothelial Corneal Dystrophy – Eyewire+

  https://eyewire.news/news/ultraviolet-light-exposure-identified-as-factor-linked-to-eye-disease-fuchs-endothelial-corneal-dystrophy

  Much research over the past decade has looked closely genetic factors that cause FECD, but until now, a study has not reported on underlying mechanism that may represent a modifiable risk factor. […] The center of the cornea is what gets light exposure, so the team postulated that UV light exposure may play a role in the disease. […] They put this to the test by exposing the central cornea in adult mice to UVA light, where they were able to induce formation of Fuchs dystrophy. […] They then discovered a novel pathway where the UVA light causes increased expression of an enzyme called CYP1B1, that jump starts an estrogen metabolite pathway that interacts with the DNA to damage it. […] This increased estrogen formation correlates with the sex-dependent differences in disease presentation, they reported. […] That is the mechanism that that explains what we have been seeing in our patients, said Dr. Jurkunas. […] Future studies from her group will look at the interplay between genetic and environmental factors to address why certain people, notably women, are more likely to develop FECD than others.

• #32 Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy | Scientific Reports

  https://www.nature.com/articles/s41598-019-52727-z

  Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. In Fuchs endothelial corneal dystrophy (FECD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ECM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. […] Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from FECD patients. We discover that miRNA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD.

• #33

  https://link.springer.com/article/10.1007/s00018-023-04714-x

  The most striking finding in the global methylation analysis was hypomethylation of F5 gene, which prompted us to examine the F5 mRNA expression. We demonstrated a~23-fold increase of F5 gene expression in CE from FECD patients compared to non-FECD controls, which was in line with the loss of methylation in the predicted enhancer/promoter at position chr1:169,554,071 (GRCh37/hg19) in the FECD group. […] The elevated level of THBD expression could not be explained by hypomethylation, since no DM-CpG sites were found in the THBD gene. […] In conclusion, significant global methylation changes in corneal endothelium from FECD patients with TCF4 CTG18.1 repeat expansion are an indisputable fact. Hypomethylation of coagulation factor V and the significant increase of its and thrombomodulin’s mRNA expression might reveal novel mechanisms in the appearance and/or progress of FECD.

• #34 Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy | Eye and Vision | Full Text

  https://eandv.biomedcentral.com/articles/10.1186/s40662-021-00246-2

  The pathogenesis of Fuchs endothelial corneal dystrophy is very complicated. Currently, corneal transplantation is an important method in the treatment of Fuchs endothelial corneal dystrophy. It is necessary to continuously explore the pathogenesis of Fuchs endothelial corneal dystrophy and establish the scientific foundations for the development of next-generation corneal therapeutics. […] Proper protein folding is critical to overall cellular functioning. Cells have a conservation mechanism in the endoplasmic reticulum (ER) that allows them to avoid protein misfolding and deal with cytotoxic misfolded proteins, of which the excessive accumulation results in ER stress. Unfolded protein response (UPR) is a pro-survival response; it reduces unfolded protein accumulation and restores normal ER function. However, if protein aggregation persists and stress cannot be resolved, the signal changes from pro-survival to pro-apoptotic.

• #35 A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation | Communications Biology

  https://www.nature.com/articles/s42003-024-06046-3

  Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. […] We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. […] Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). […] AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. […] Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

• #36 A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation | Communications Biology

  https://www.nature.com/articles/s42003-024-06046-3

  These subunits form the laminin-511 heterotrimer (LM511; also called laminin-10), implicating an important role for LM511 in CEC maintenance and FECD pathogenesis. […] Our structural analysis suggests that the variants associated with FECD may destabilize LM511 through altered inter-domain interactions, rather than through structural changes of the mutated domains. […] Our findings further highlight the importance of dysregulated ion balance in FECD and indicate a pleiotropic connection to kidney function at TCF4. […] The convergence of evidence across FECD and serum and urinary ionic concentrations suggests that the pathogenicity of CTG18.1 expansions is mediated through dysregulated ion balance in CECs.

• #37 Pathological molecular mechanism of symptomatic late-onset Fuchs endothelial corneal dystrophy by bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197750

  Fuchs endothelial corneal dystrophy (FECD) is a degenerative disease characterized by corneal endothelial decompensation. FECD causes corneal stromal and epithelial edema and progressively develops into bullous keratopathy, which can eventually lead to blindness. However, the exact pathogenesis is unknown. […] We found that cell senescence, reactive oxygen species (ROS), the extracellular matrix (ECM), epithelial-mesenchymal transition (EMT) and immune response-related genes play an important role in the pathological development of symptomatic late-onset FECD. […] This study enhances our understanding of the molecular mechanism of FECD pathogenesis and will improve the diagnostics and therapy of FECD patients in the future. […] The exact pathogenesis is unknown. […] CECs are in cell cycle arrest and hardly proliferate in vivo. Therefore, corneal endothelial damage and losses in FECD are permanent and irreversible.

• #38 Pathological molecular mechanism of symptomatic late-onset Fuchs endothelial corneal dystrophy by bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197750

  According to the above results, we plotted the possible signaling pathway network. […] Therefore, for FECD nonsurgical therapy, we might consider therapeutic strategies on anti-inflammatory, anti-ROS and anti-EMT activities, as well as inhibition of NF-B activity and PI3K activity. […] The possible pathological and molecular mechanisms of symptomatic late-onset FECD were preliminarily analyzed and diagrammatized.

• #39 Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy | Eye and Vision | Full Text

  https://eandv.biomedcentral.com/articles/10.1186/s40662-021-00246-2

  Fuchs endothelial corneal dystrophy is a hereditary disease and the most frequent cause of corneal transplantation in the worldwide. Its main clinical signs are an accelerated decrease in the number of endothelial cells, thickening of Descemets membrane and formation of guttae in the extracellular matrix. The corneas ability to maintain stromal dehydration is impaired, causing painful epithelial bullae and loss of vision at the point when the amount of corneal endothelial cells cannot be compensated. At present, apart from corneal transplantation, there is no other effective treatment that prevents blindness. […] The molecular mechanisms associated with Fuchs endothelial corneal dystrophy, such as endoplasmic reticulum stress and unfolded protein response pathway, oxidative stress, mitochondrial dysregulation pathway, apoptosis pathway, mitophagy, epithelial-mesenchymal transition pathway, RNA toxicity and repeat-associated non-ATG translation, and other pathogenesis, were then explored.

• #40 Fuchs endothelial corneal dystrophy: for professionals – Gene Vision

  https://gene.vision/knowledge-base/fuchs-endothelial-corneal-dystrophy-for-doctors/

  Mutations in all the identified genes and chromosomal loci are inherited in an autosomal dominant manner. The genotypes associated with late-onset Fuchs endothelial corneal dystrophy (FECD) have incomplete penetrance with variable expressivity while COL8A2 mutations causing early-onset FECD are more highly penetrant. […] Oxidative stress, endoplasmic reticulum stress (from accumulation of misfolded proteins) and apoptosis have been implicated as underlying disease mechanisms of FECD. Several drugs have been identified as potential protective factors against these pathologic responses: […] Ex vivo studies of human FECD corneas have demonstrated that AONs targeting the CTG18.1 allele in TCF4 are able to ameliorate disease-associated markers of RNA toxicity as a result of the trinucleotide repeat expansion. […] Utilisation of the CRISPR/Cas9 technology to treat FECD due to CTG trinucleotide repeat expansion has amassed interest following the successful treatment of a rodent model of Huntingtons disease, a neurodegenerative disorder associated with trinucleotide repeat expansion.

• #41 Design Therapeutics Phase 1 Data Shows Promise for Novel FECD Eye Drop Treatment | DSGN Stock News

  https://www.stocktitan.net/news/DSGN/design-therapeutics-to-present-phase-1-data-for-fuchs-endothelial-jmcbpg3nsg57.html

  Design Therapeutics will present Phase 1 safety data for its novel FECD eye drop therapy, advancing toward Phase 2 trials for an untreated genetic eye disease. […] DT-168 is a GeneTAC small molecule, formulated as an eye drop, that is designed to selectively target the CTG repeat expansion in the TCF4 gene and reduce the expression of the mutant gene product that causes corneal endothelial cell dysfunction leading to FECD. […] DT-168’s mechanism of action is particularly notable – it specifically targets the CTG repeat expansion in the TCF4 gene that underlies the pathology in many FECD patients. By reducing expression of the mutant gene product, it aims to address the genetic root cause rather than merely managing symptoms. […] The significance of this program stems from the current treatment landscape – FECD has no disease-modifying treatments available, with many patients ultimately requiring corneal transplant surgery. An eye drop that could potentially restore endothelial function would represent a major advancement in treatment paradigm.

Zobacz więcej