Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond
Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6101 |
| _version_ | 1797607887115124736 |
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| author | Roland N. Wagner Michael Wießner Andreas Friedrich Johanna Zandanell Hannelore Breitenbach-Koller Johann W. Bauer |
| author_facet | Roland N. Wagner Michael Wießner Andreas Friedrich Johanna Zandanell Hannelore Breitenbach-Koller Johann W. Bauer |
| author_sort | Roland N. Wagner |
| collection | DOAJ |
| description | Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa. |
| first_indexed | 2024-03-11T05:35:53Z |
| format | Article |
| id | doaj.art-7a7c6fe34b3049b8b3b1482dac958bfc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T05:35:53Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7a7c6fe34b3049b8b3b1482dac958bfc2023-11-17T16:46:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01247610110.3390/ijms24076101Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and BeyondRoland N. Wagner0Michael Wießner1Andreas Friedrich2Johanna Zandanell3Hannelore Breitenbach-Koller4Johann W. Bauer5Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Biosciences, University of Salzburg, 5020 Salzburg, AustriaDepartment of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, AustriaNonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.https://www.mdpi.com/1422-0067/24/7/6101translational readthroughpremature termination codon (PTC)nonsense suppression therapyepidermolysis bullosa (EB) |
| spellingShingle | Roland N. Wagner Michael Wießner Andreas Friedrich Johanna Zandanell Hannelore Breitenbach-Koller Johann W. Bauer Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond International Journal of Molecular Sciences translational readthrough premature termination codon (PTC) nonsense suppression therapy epidermolysis bullosa (EB) |
| title | Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond |
| title_full | Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond |
| title_fullStr | Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond |
| title_full_unstemmed | Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond |
| title_short | Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond |
| title_sort | emerging personalized opportunities for enhancing translational readthrough in rare genetic diseases and beyond |
| topic | translational readthrough premature termination codon (PTC) nonsense suppression therapy epidermolysis bullosa (EB) |
| url | https://www.mdpi.com/1422-0067/24/7/6101 |
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