Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy
Abstract Trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene represents the most prevalent genetic risk factor for Fuchs endothelial corneal dystrophy (FECD) and may cause dysfunction of splicing regulators. We investigated differential alternative splicing (DAS) events in...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-92119-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849726251951980544 |
|---|---|
| author | Taichi Yuasa Yuichi Tokuda Masakazu Nakano Kei Tashiro Theofilos Tourtas Ursula Schlötzer-Schrehardt Friedrich Kruse Noriko Koizumi Naoki Okumura |
| author_facet | Taichi Yuasa Yuichi Tokuda Masakazu Nakano Kei Tashiro Theofilos Tourtas Ursula Schlötzer-Schrehardt Friedrich Kruse Noriko Koizumi Naoki Okumura |
| author_sort | Taichi Yuasa |
| collection | DOAJ |
| description | Abstract Trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene represents the most prevalent genetic risk factor for Fuchs endothelial corneal dystrophy (FECD) and may cause dysfunction of splicing regulators. We investigated differential alternative splicing (DAS) events in corneal endothelial cells (CECs) from FECD patients with and without TCF4 TNR expansion through RNA-Seq analysis. We identified distinct splicing profiles among control subjects, FECD patients with TNR expansion, and FECD patients without TNR expansion. Skipped Exon events constituted approximately 50% of all DAS events across all comparisons, with the remaining events distributed among alternative 3’ splice site, alternative 5’ splice site, mutually exclusive exon, and retained intron categories. Motif analysis in FECD patients with TNR expansion revealed several RNA-binding proteins, including MBNL1, as potential regulators of these splicing alterations. Computational analysis demonstrated that 34% of Skipped Exon events in the TNR expansion group significantly impacted protein structure. This comprehensive analysis revealed distinct alternative splicing signatures in FECD, particularly in cases with TNR expansion, suggesting a crucial role for aberrant splicing in FECD pathogenesis. |
| format | Article |
| id | doaj-art-6af6ec9121c0418eade004de83abf2d4 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-6af6ec9121c0418eade004de83abf2d42025-08-20T03:10:14ZengNature PortfolioScientific Reports2045-23222025-04-0115111210.1038/s41598-025-92119-0Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophyTaichi Yuasa0Yuichi Tokuda1Masakazu Nakano2Kei Tashiro3Theofilos Tourtas4Ursula Schlötzer-Schrehardt5Friedrich Kruse6Noriko Koizumi7Naoki Okumura8Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha UniversityDepartment of Genomic Medical Sciences, Kyoto Prefectural University of MedicineDepartment of Genomic Medical Sciences, Kyoto Prefectural University of MedicineDepartment of Genomic Medical Sciences, Kyoto Prefectural University of MedicineDepartment of Ophthalmology, University of Erlangen-NürnbergDepartment of Ophthalmology, University of Erlangen-NürnbergDepartment of Ophthalmology, University of Erlangen-NürnbergDepartment of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha UniversityDepartment of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha UniversityAbstract Trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene represents the most prevalent genetic risk factor for Fuchs endothelial corneal dystrophy (FECD) and may cause dysfunction of splicing regulators. We investigated differential alternative splicing (DAS) events in corneal endothelial cells (CECs) from FECD patients with and without TCF4 TNR expansion through RNA-Seq analysis. We identified distinct splicing profiles among control subjects, FECD patients with TNR expansion, and FECD patients without TNR expansion. Skipped Exon events constituted approximately 50% of all DAS events across all comparisons, with the remaining events distributed among alternative 3’ splice site, alternative 5’ splice site, mutually exclusive exon, and retained intron categories. Motif analysis in FECD patients with TNR expansion revealed several RNA-binding proteins, including MBNL1, as potential regulators of these splicing alterations. Computational analysis demonstrated that 34% of Skipped Exon events in the TNR expansion group significantly impacted protein structure. This comprehensive analysis revealed distinct alternative splicing signatures in FECD, particularly in cases with TNR expansion, suggesting a crucial role for aberrant splicing in FECD pathogenesis.https://doi.org/10.1038/s41598-025-92119-0 |
| spellingShingle | Taichi Yuasa Yuichi Tokuda Masakazu Nakano Kei Tashiro Theofilos Tourtas Ursula Schlötzer-Schrehardt Friedrich Kruse Noriko Koizumi Naoki Okumura Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy Scientific Reports |
| title | Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy |
| title_full | Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy |
| title_fullStr | Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy |
| title_full_unstemmed | Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy |
| title_short | Comprehensive analysis of splicing variants in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy |
| title_sort | comprehensive analysis of splicing variants in corneal endothelial cells of patients with fuchs endothelial corneal dystrophy |
| url | https://doi.org/10.1038/s41598-025-92119-0 |
| work_keys_str_mv | AT taichiyuasa comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT yuichitokuda comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT masakazunakano comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT keitashiro comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT theofilostourtas comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT ursulaschlotzerschrehardt comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT friedrichkruse comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT norikokoizumi comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy AT naokiokumura comprehensiveanalysisofsplicingvariantsincornealendothelialcellsofpatientswithfuchsendothelialcornealdystrophy |