Pathological molecular mechanism of symptomatic late-onset Fuchs endothelial corneal dystrophy by bioinformatic analysis

Cui, Zekai; Zeng, Qiaolang; Guo, Yanjie; Liu, Shiwei; Wang, Peiyuan; Xie, Mengyuan; Chen, Jiansu

doi:10.1371/journal.pone.0197750

Cited by 19 publications

(19 citation statements)

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“…In the clinic, late stage FECD is a disease of cellular degeneration and aberrant extracellular matrix deposition ( Figure 10). Previous studies of FECD_REP tissue have supported activation of the fibrosis pathway as a primary cause for late stage disease pathology (30). We confirmed fibrosis as the highest ranked canonical pathway in both late stage FECD_REP and FECD_NR ( Figure 8A).…”

Section: Expanded Cug Mutant Rna Causes Splicing Changes In Presymptosupporting

confidence: 81%

“…Overexpression of MBNL1 can reverse RNA missplicing and myotonia in a DM1 mouse model (31). MBNL is also associated with mutant CUG RNA in FECD cells and tissue (28)(29)(30). Blocking the CUG repeat region using antisense oligonucleotides can reverse missplicing in DM1 (caused by a CUG repeat within the DMPK gene) (48-51) and FECD (44,52) tissues.…”

Section: Discussionmentioning

confidence: 99%

“…CUG repeat RNA is known to bind the splicing factors muscleblind-like 1 and 2 (MBNL1 and MNBL2) (24)(25)(26)(27). Previous studies have proposed that sequestration of MBNL1 and MBNL2 reduces levels of available MBNL protein, causing the changes of splicing observed in tissue from FECD_REP patients (28)(29)(30) and in patients with myotonic dystrophy who possess expanded CUG repeats within 3'-untranslated region of the DMPK gene (24,25,31).…”

Section: Changes In Alternative Splicing Triggered By the Expanded Rementioning

confidence: 99%

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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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Section: Expanded Cug Mutant Rna Causes Splicing Changes In Presymptosupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Changes In Alternative Splicing Triggered By the Expanded Rementioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…In the clinic, late stage FECD is a disease of cellular degeneration and aberrant ECM deposition (Figure 10 ). Previous studies of FECD_REP tissue have supported activation of the fibrosis pathway as a primary cause for late stage disease pathology ( 33 ). We confirmed fibrosis as the highest ranked canonical pathway in both late stage FECD_REP and FECD_NR (Figure 8A ).…”

Section: Discussionmentioning

confidence: 92%

Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease

Chu

Liang

et al. 2020

Nucleic Acids Research

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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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“…Gene expression analysis using microarray or RNA-sequencing revealed the unique gene expression profile with differentially expressed genes comparing Fuchs endothelial corneal dystrophy patients with controls. Several studies using gene expression analysis have revealed the molecular mechanism of FECD disease [ 15 , 16 ]. We speculate that these unique gene expression signatures can contribute to elements of underlying disease pathogenesis and progression, such as upregulation in inflammation and downregulation in glycolysis.…”

Section: Introductionmentioning

confidence: 99%

Incorporating Differential Gene Expression Analysis with Predictive Biomarkers to Identify Novel Therapeutic Drugs for Fuchs Endothelial Corneal Dystrophy

Wen

Gallo

Huang

et al. 2021

Journal of Ophthalmology

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Purpose. Based on the differential gene expression analysis for predictive biomarkers with RNA-Sequencing data from Fuchs endothelial corneal dystrophy (FECD) patients, we are aiming to evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify novel pharmacotherapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotype in FECD. Methods. A publicly available RNA-seq dataset was used to compare corneal endothelial specimens from controls and patients with FECD. Based on the differential gene expression analysis for predictive biomarkers, we evaluated the efficacy of LINCS perturbagen prediction software to identify novel therapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotypes in FECD. Results. The RNA-seq dataset of the corneal endothelial cells from FECD patients revealed the differential gene expression signatures of FECD. Many of the differential expressed genes are related to canonical pathways of the FECD pathogenesis, such as extracellular matrix reorganization and immunological response. The expression levels of genes VSIG2, IL18, and ITGB8 were significantly increased in FECD compared with control. Meanwhile, the expression levels of CNGA3, SMOX, and CERS1 were significantly lower in the FECD than in control. We employed LINCS L1000 Characteristic Direction Signature Search Engine (L1000-CDS2) to investigate pathway-based molecular treatment. L1000-CDS2 predicted that small molecule drugs such as histone deacetylase (HDAC) inhibitors might be a potential candidate to reverse the pathological gene expression signature in FECD. Conclusions. Based on differential gene expression signatures, several candidate drugs have been identified to reverse the disease phenotypes in FECD. Gene expression signature with LINCS small molecule prediction software can discover novel preclinical drug candidates for FECD.

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Pathological molecular mechanism of symptomatic late-onset Fuchs endothelial corneal dystrophy by bioinformatic analysis

Cited by 19 publications

References 50 publications

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

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

Analyzing pre-symptomatic tissue to gain insights into the molecular and mechanistic origins of late-onset degenerative trinucleotide repeat disease

Incorporating Differential Gene Expression Analysis with Predictive Biomarkers to Identify Novel Therapeutic Drugs for Fuchs Endothelial Corneal Dystrophy

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