Identification of Circulating Fibrocytes and Dendritic Derivatives in Corneal Endothelium of Patients with Fuchs' Dystrophy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75676 | GEO | 2017/01/24
SECONDARY ACCESSION(S): PRJNA305030
REPOSITORIES: GEO
Similar Datasets
Project description:PURPOSE: Fuchs’ endothelial corneal dystrophy (FECD) is a degenerative eye disorder affecting 4% of Americans older than 40. It is the leading indication for corneal endothelial (CE) transplantation for which there is a global donor shortage. This study aimed to gain further insight into the pathophysiology of FECD and identify targets for nonsurgical therapy. METHODS: CE from patients with late-onset FECD was compared with that of normal controls using microarray expression analysis (n = 4 FECD, n = 4 normal), reverse transcriptase quantitative PCR (n = 9 FECD, n = 8 normal), and immunohistology (n = 55 FECD, n = 15 normal). RESULTS: This led to the identification of circulating fibrocytes and their dendritic derivatives in all examined CE samples with FECD (in all clinical stages of symptomatic FECD and independent of prior cataract surgery). These cells were not present in normal CE. In this study we characterize their morphology, protein expression profile, number, and localization within the CE layer of patients with FECD. CONCLUSIONS: Circulating fibrocytes and their dendritic derivatives are a new aspect of FECD that deserves further investigation. Because they are known to cause fibrosis in a variety of organs, they may play a similar role in FECD and might be a valuable target for nonsurgical therapy.
2017-01-24 | GSE74123 | GEO
Project description:PURPOSE: Fuchs’ endothelial corneal dystrophy (FECD) is a degenerative eye disorder affecting 4% of Americans older than 40. It is the leading indication for corneal endothelial (CE) transplantation for which there is a global donor shortage. This study aimed to gain further insight into the pathophysiology of FECD and identify targets for nonsurgical therapy. METHODS: CE from patients with late-onset FECD was compared with that of normal controls using microarray expression analysis (n = 4 FECD, n = 4 normal), reverse transcriptase quantitative PCR (n = 9 FECD, n = 8 normal), and immunohistology (n = 55 FECD, n = 15 normal). RESULTS: This led to the identification of circulating fibrocytes and their dendritic derivatives in all examined CE samples with FECD (in all clinical stages of symptomatic FECD and independent of prior cataract surgery). These cells were not present in normal CE. In this study we characterize their morphology, protein expression profile, number, and localization within the CE layer of patients with FECD. CONCLUSIONS: Circulating fibrocytes and their dendritic derivatives are a new aspect of FECD that deserves further investigation. Because they are known to cause fibrosis in a variety of organs, they may play a similar role in FECD and might be a valuable target for nonsurgical therapy.
2017-01-24 | GSE75675 | GEO
Project description:PURPOSE: Fuchs’ endothelial corneal dystrophy (FECD) is a degenerative eye disorder affecting 4% of Americans older than 40. It is the leading indication for corneal endothelial (CE) transplantation for which there is a global donor shortage. This study aimed to gain further insight into the pathophysiology of FECD and identify targets for nonsurgical therapy. METHODS: CE from patients with late-onset FECD was compared with that of normal controls using microarray expression analysis (n = 4 FECD, n = 4 normal), reverse transcriptase quantitative PCR (n = 9 FECD, n = 8 normal), and immunohistology (n = 55 FECD, n = 15 normal). RESULTS: This led to the identification of circulating fibrocytes and their dendritic derivatives in all examined CE samples with FECD (in all clinical stages of symptomatic FECD and independent of prior cataract surgery). These cells were not present in normal CE. In this study we characterize their morphology, protein expression profile, number, and localization within the CE layer of patients with FECD. CONCLUSIONS: Circulating fibrocytes and their dendritic derivatives are a new aspect of FECD that deserves further investigation. Because they are known to cause fibrosis in a variety of organs, they may play a similar role in FECD and might be a valuable target for nonsurgical therapy.
2017-01-24 | GSE75674 | GEO
Project description:Identification of Circulating Fibrocytes and Dendritic Derivatives in Corneal Endothelium of Patients with Fuchs' Dystrophy
| PRJNA305030 | ENA
Project description:Fuchs endothelial corneal dystrophy (FECD) is a bilateral inherited eye disease with advanced forms only treatable by corneal transplantation. The pathogenesis of FECD has not been worked out yet, however, trinucleotide repeat polymorphism CTG18.1 in the TCF4 gene has recently been associated with late-onset FECD. Gene expression profiling of corneal endothelium with and without this expansion can help elucidate molecular mechanisms of the disease development. Current data article represents whole transcriptome profiles of corneal endothelium obtained from 12 patients with FECD and 6 control tissues from eye bank donors. RNA sequencing data is available at NCBI Sequence Read Archive under Accession No. PRJNA524323. In addition, each patient and donor were genotyped for CTG18.1 expansion and the corresponding numbers of CTG repeats in the TCF4 gene are provided within this article. The dataset includes samples from FECD patients both with and without CTG18.1 expansion.
| S-EPMC6558234 | biostudies-literature
Project description:Expansion of CTG trinucleotide repeats (TNR) in the transcription factor 4 (TCF4) gene is highly associated with Fuchs Endothelial Corneal Dystrophy (FECD). Due to limitations in the availability of DNA from diseased corneal endothelium, sizing of CTG repeats in FECD patients has typically been determined using DNA samples isolated from peripheral blood leukocytes. However, it is non-feasible to extract enough DNA from surgically isolated FECD corneal endothelial tissue to determine repeat length based on current technology. To circumvent this issue, total RNA was isolated from FECD corneal endothelium and sequenced using long-read sequencing. Southern blotting of DNA samples isolated from primary cultures of corneal endothelium from these same affected individuals was also assessed. Both long read sequencing and Southern blot analysis showed significantly longer CTG TNR expansion (>1000 repeats) in the corneal endothelium from FECD patients than those characterized in leukocytes from the same individuals (<90 repeats). Our findings suggest that the TCF4 CTG repeat expansions in the FECD corneal endothelium are much longer than those found in leukocytes.
| S-EPMC8638873 | biostudies-literature
Project description:PURPOSE:To report the observation of a triple corneal dystrophy association consisting of keratoconus (KC), epithelial basement membrane corneal dystrophy (EBMCD) and Fuchs' endothelial corneal dystrophy (FECD). METHODS:A 55-year-old male patient was referred to our cornea service for blurred vision and recurrent foreign body sensation. He reported bilateral recurrent corneal erosions with diurnal visual fluctuations. He underwent corneal biomicroscopy, Scheimpflug tomography, in vivo HRT confocal laser scanning microscopy and genetic testing for TGFBI and ZEB1 mutations using direct DNA sequencing. RESULTS:Biomicroscopic examination revealed the presence of subepithelial central and paracentral corneal opacities. The endothelium showed a bilateral flecked appearance, and the posterior corneal curvature suggested a possible concomitant ectatic disorder. Corneal tomography confirmed the presence of a stage II KC in both eyes. In vivo confocal laser scanning microscopy revealed a concomitant bilateral EBMCD with hyperreflective deposits in basal epithelial cells, subbasal Bowman's layer microfolds and ridges with truncated subbasal nerves as pseudodendritic elements. Stromal analysis revealed honeycomb edematous areas, and the endothelium showed a strawberry surface configuration typical of FECD. The genetic analysis resulted negative for TGFBI mutations and positive for a heterozygous mutation in exon 7 of the gene ZEB1. CONCLUSION:This is the first case reported in the literature in which KC, EBMCD and FECD are present in the same patient and associated with ZEB1 gene mutation. The triple association was previously established by means of morphological analysis of the cornea using corneal Scheimpflug tomography and in vivo HRT II confocal laser scanning microscopy.
| S-EPMC4209271 | biostudies-literature
Project description:PURPOSE:To evaluate the feasibility of 3D anterior segment optical coherence tomography (AS-OCT) for the detection of corneal endothelial features in patients with Fuchs' Endothelial Corneal Dystrophy (FECD). METHODS:Twenty patients with clinical diagnosis of FECD (group A), and 20 control subjects (group B) were enrolled. In all patients a complete ophthalmological examination was performed, including best corrected visual acuity (BCVA), slit lamp examination for subjective grading of FECD and corneal endothelial specular microscopy. A 512x128 AS-OCT cube centered on the corneal apex was performed, and then the inner surface of the cornea was visualized and analyzed individually. RESULTS:Overall, the study participants were adults (mean age was 57.35 ± 8.45 years [mean ± SD] 80% female) with a BCVA ranged from 1.3 to 0 LogMAR. The OCT analysis disclosed three different patterns of the corneal endothelium (1, 2, 3) according to the signal distribution and the level of reflectivity: a homogenous, hypo-reflective surface (pattern 1); the presence of hyper-reflective orange-yellowish points (pattern 2); and a mottled appearance with a variable number of hyper-reflective areas (pattern 3). The distributions of these morphological models in the two populations were as follows: patterns 1, 2 and 3 were observed respectively in 0%, 80%, and 20% of patients in group A, and in 80%, 20% and 0% of subjects in group B. Correlation analysis unveiled a positive relationship between OCT corneal endothelium reflectivity and the clinical severity score (assessed with biomicroscopy), as well as an inverse relationship between the OCT pattern and the integrity of corneal endothelium. CONCLUSION:3D AS-OCT is a useful tool in investigation of endothelial features and therefore may represent a valuable support in the setting of FECD diagnosis and staging.
| S-EPMC6264151 | biostudies-literature
Project description:Purpose:CTG trinucleotide repeat (TNR) expansion in an intron of the TCF4 gene is the most common genetic variant associated with Fuchs' endothelial corneal dystrophy (FECD). Although several mechanisms have been implicated in the disease process, their exact pathophysiologic importance is unclear. To understand events leading from TCF4 TNR expansion to disease phenotype, we characterized splicing, gene expression, and exon sequence changes in a rare cohort of patients with TNR expansions but no phenotypic FECD (RE+/FECD-). Methods:Corneal endothelium and blood were collected from patients undergoing endothelial keratoplasty for non-FECD corneal edema. Total RNA was isolated from corneal endothelial tissue (n = 3) and used for RNASeq. Gene splicing and expression was assessed by Mixture of Isoforms (MISO) and MAP-RSeq software. Genomic DNA was isolated from blood mononuclear cells and used for whole genome exome sequencing. Base calling was performed using Illumina's Real-Time Analysis. Results:Three genes (MBNL1, KIF13A, AKAP13) that were previously identified as misspliced in patients with a CTG TNR expansion and FECD disease (RE+/FECD+) were found normally spliced in RE+/FECD- samples. Gene expression differences in pathways associated with the innate immune response, cell signaling (e.g., TGF?, WNT), and cell senescence markers were also identified between RE+/FECD- and RE+/FECD+ groups. No consistent genetic variants were identified in RE+/FECD- patient exomes. Conclusions:Identification of novel splicing patterns and differential gene expression in RE+/FECD- samples provides new insights and more relevant gene targets that may be protective against FECD disease in vulnerable patients with TCF4 CTG TNR expansions.
| S-EPMC6716950 | biostudies-literature
Project description:PurposeRNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs' endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium.MethodsFECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA.ResultsFECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P < 0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients.ConclusionsFECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.
| S-EPMC6005624 | biostudies-literature