CTG18.1 repeat expansion may reduce TCF4 gene expression in corneal endothelial cells of German patients with Fuchs’ dystrophy

Foja, Sabine; Luther, M.; Hoffmann, Katrin; Rupprecht, Andreas; Gruenauer-Kloevekorn, Claudia

doi:10.1007/s00417-017-3697-7

Cited by 28 publications

(34 citation statements)

References 45 publications

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“…Marker alleles were not found in 21 FECD patients; thus, exome sequencing for those particular patients is warranted. 18,19,22,35 76.4-77.0 21,26 17.3-34.1 37,40 43.9 41 25.5 42 72…”

Section: Discussionmentioning

confidence: 99%

“…Association of the intronic single-nucleotide Copyright 2018 The Authors iovs.arvojournals.org j ISSN: 1552-5783 polymorphism (SNP) rs613872 with FECD was discovered in the Genome-Wide Association Study (GWAS) performed by Baratz et al 12 Later, this association was confirmed in a number of studies involving more than a thousand people. [13][14][15][16][17][18][19][20][21] Other SNPs in the TCF4 gene are associated with FECD but to a lesser extent, namely, rs17595731, rs9954153, and rs2286812. 12,14,15 Wieben et al 22 found another important relationship between FECD and the expansion of trinucleotide repeats in the TCF4 gene intron CTG18.1: The expansion of trinucleotide repeats appeared to be a more specific marker of FECD than rs613872 (96% vs. 79%).…”

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confidence: 99%

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CTG18.1 Expansion is the Best Classifier of Late-Onset Fuchs' Corneal Dystrophy Among 10 Biomarkers in a Cohort From the European Part of Russia

Skorodumova

Belodedova

Antonova

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To assess the occurrence and diagnostic performance of nine single-nucleotide variants (SNVs) in the TCF4, SLC4A11, LOXHD1, and AGBL1 genes and the CTG18.1 trinucleotide repeat expansion in a Russian cohort of Fuchs' endothelial corneal dystrophy (FECD) patients. METHODS. This retrospective case-control study included 100 patients diagnosed with FECD (cases) and 100 patients with cataracts (controls). Blood DNA was used to perform PCR and subsequent Sanger sequencing of rs613872 and rs17595731 in TCF4, c.99-100delTC, rs267607065, rs267607064, and rs267607066 in SLC4A11, rs113444922 in LOXHD1, and rs181958589 and rs185919705 in AGBL1. The number of CTG18.1 trinucleotide repeats was determined by a combination of conventional PCR or triplet primed PCR with fragment analysis. RESULTS. At least one rs613872 marker allele was found in 78% of FECD patients and 21% of controls, and at least one rs17595731 marker allele was found in 14% and 2%, respectively. CTG18.1 trinucleotide expansion (>40 repeats) was detected in 72% of FECD patients and 5% of controls. Marker alleles of the tested SNVs in SLC4A11, LOXHD1, and rs185919705 in AGBL1 were not found in our FECD cohort. One FECD patient carried the marker allele of the rs181958589 SNV. Analysis of the diagnostic performance of individual markers in TCF4 and their combinations showed that the CTG18.1 repeat expansion was the best classifier for FECD (AUC ¼ 0.84). CONCLUSIONS. Patients carrying CTG18.1 repeat expansion constituted a high proportion of the Russian FECD cohort; therefore, this marker is suitable for development of diagnostic and therapeutic approaches.

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“…Marker alleles were not found in 21 FECD patients; thus, exome sequencing for those particular patients is warranted. 18,19,22,35 76.4-77.0 21,26 17.3-34.1 37,40 43.9 41 25.5 42 72…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CTG18.1 Expansion is the Best Classifier of Late-Onset Fuchs' Corneal Dystrophy Among 10 Biomarkers in a Cohort From the European Part of Russia

Skorodumova

Belodedova

Antonova

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Interestingly, an increase in the levels of TCF4 transcripts encoded by downstream alternative 5′ exons distal to the CTG TNR was also noted, which may indicate a compensatory mechanism to rescue the levels of TCF4 protein arising from the deficit of transcripts encoding TCF4-C. This compensation phenomenon needs to be considered when studying TCF4 expression levels in FECD and other diseases connected with the TCF4 intronic CTG TNR and could explain why different research groups have published contradictory results concerning changes in TCF4 levels when studying FECD 19 – 22 . Our results indicate that the levels of TCF4 transcripts change bidirectionally in response to an expanded CTG TNR—transcripts beginning near the repeat region decline just as Foja et al reported 19 while certain transcripts beginning downstream of the repeat region increase as reported here, and mask the decrease of long TCF4 transcripts.…”

Section: Discussionmentioning

confidence: 99%

“…This compensation phenomenon needs to be considered when studying TCF4 expression levels in FECD and other diseases connected with the TCF4 intronic CTG TNR and could explain why different research groups have published contradictory results concerning changes in TCF4 levels when studying FECD 19 – 22 . Our results indicate that the levels of TCF4 transcripts change bidirectionally in response to an expanded CTG TNR—transcripts beginning near the repeat region decline just as Foja et al reported 19 while certain transcripts beginning downstream of the repeat region increase as reported here, and mask the decrease of long TCF4 transcripts. As the expression of different TCF4 transcripts decline and rise simultaneously the overall TCF4 levels may not change significantly in FECD as has been reported by Mootha et al 21 and Ołdak et al 22 .…”

Section: Discussionmentioning

confidence: 99%

“…Studies on the connection between the TCF4 CTG TNR expansion and the mRNA levels of TCF4 transcripts spanning the TCF4 CTG TNR region have produced contradictory results. A study by Foja et al 19 reported that TCF4 CTG TNR expansion is connected with a reduction in the levels of TCF4 transcripts beginning in the proximity of the CTG TNR, whereas a study by Okumura et al 20 has reported that TCF4 CTG TNR expansion is connected with an increase in overall TCF4 levels and in the levels of TCF4 transcripts beginning in proximity of the CTG TNR. Two other studies 21 , 22 have reported no effect of the CTG TNR expansion on total TCF4 mRNA levels.…”

Section: Introductionmentioning

confidence: 99%

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The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters

Sirp

Leite

Tuvikene

et al. 2020

Sci Rep

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The CTG trinucleotide repeat (TNR) expansion in Transcription factor 4 (TCF4) intron 3 is the main cause of Fuchs’ endothelial corneal dystrophy (FECD) and may confer an increased risk of developing bipolar disorder (BD). Usage of alternative 5′ exons for transcribing the human TCF4 gene results in numerous TCF4 transcripts which encode for at least 18 N-terminally different protein isoforms that vary in their function and transactivation capability. Here we studied the TCF4 region containing the CTG TNR and characterized the transcription initiation sites of the nearby downstream 5′ exons 4a, 4b and 4c. We demonstrate that these exons are linked to alternative promoters and show that the CTG TNR expansion decreases the activity of the nearby downstream TCF4 promoters in primary cultured neurons. We confirm this finding using two RNA sequencing (RNA-seq) datasets of corneal endothelium from FECD patients with expanded CTG TNR in the TCF4 gene. Furthermore, we report an increase in the expression of various other TCF4 transcripts in FECD, possibly indicating a compensatory mechanism. We conclude that the CTG TNR affects TCF4 expression in a transcript-specific manner both in neurons and in the cornea.

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DNA methylation changes and increased mRNA expression of coagulation proteins, factor V and thrombomodulin in Fuchs endothelial corneal dystrophy

Westin

Landfors

Giannopoulos

et al. 2023

Cell. Mol. Life Sci.

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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. It is unknown whether CTG18.1 expansions affect global methylation including TCF4 gene in CE or whether global CE methylation changes at advanced age. Using genome-wide DNA methylation array, we investigated methylation in CE from FECD patients with CTG18.1 expansions and studied the methylation in healthy CE at different ages. 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. The most hypermethylated site was in a predicted promoter of aquaporin 1 (AQP1) gene, and the most hypomethylated site was in a predicted promoter of coagulation factor V (F5 for gene, FV for protein). In FECD, AQP1 mRNA expression was variable, while F5 gene expression showed a ~ 23-fold increase. FV protein was present in both healthy and affected CE. Further gene expression analysis of coagulation factors interacting with FV revealed a ~ 34-fold increase of thrombomodulin (THBD). THBD protein was detected only in CE from FECD patients. Additionally, we observed an age-dependent hypomethylation in elderly healthy CE.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.

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CTG18.1 repeat expansion may reduce TCF4 gene expression in corneal endothelial cells of German patients with Fuchs’ dystrophy

Cited by 28 publications

References 45 publications

CTG18.1 Expansion is the Best Classifier of Late-Onset Fuchs' Corneal Dystrophy Among 10 Biomarkers in a Cohort From the European Part of Russia

CTG18.1 Expansion is the Best Classifier of Late-Onset Fuchs' Corneal Dystrophy Among 10 Biomarkers in a Cohort From the European Part of Russia

The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters

DNA methylation changes and increased mRNA expression of coagulation proteins, factor V and thrombomodulin in Fuchs endothelial corneal dystrophy

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