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Treatment of ARS deficiencies with specific amino acids
PURPOSE: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244667/ https://www.ncbi.nlm.nih.gov/pubmed/34194004 http://dx.doi.org/10.1038/s41436-021-01249-z |
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author | Kok, Gautam Tseng, Laura Schene, Imre F. Dijsselhof, Monique E. Salomons, Gajja Mendes, Marisa I. Smith, Desiree E. C. Wiedemann, Arnaud Canton, Marie Feillet, François de Koning, Tom J. Boothe, Megan Dean, Joy Kassel, Rachel Ferreira, Elise A. van den Born, Margreet Nieuwenhuis, Edward E. S. Rehmann, Holger Terheggen-Lagro, Suzanne W. J. van Karnebeek, Clara D. M. Fuchs, Sabine A. |
author_facet | Kok, Gautam Tseng, Laura Schene, Imre F. Dijsselhof, Monique E. Salomons, Gajja Mendes, Marisa I. Smith, Desiree E. C. Wiedemann, Arnaud Canton, Marie Feillet, François de Koning, Tom J. Boothe, Megan Dean, Joy Kassel, Rachel Ferreira, Elise A. van den Born, Margreet Nieuwenhuis, Edward E. S. Rehmann, Holger Terheggen-Lagro, Suzanne W. J. van Karnebeek, Clara D. M. Fuchs, Sabine A. |
author_sort | Kok, Gautam |
collection | PubMed |
description | PURPOSE: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities. METHODS: In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments. RESULTS: Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (P(LARS) and P(FARSB)), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2–2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency. CONCLUSION: For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation. |
format | Online Article Text |
id | pubmed-8244667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-82446672021-07-01 Treatment of ARS deficiencies with specific amino acids Kok, Gautam Tseng, Laura Schene, Imre F. Dijsselhof, Monique E. Salomons, Gajja Mendes, Marisa I. Smith, Desiree E. C. Wiedemann, Arnaud Canton, Marie Feillet, François de Koning, Tom J. Boothe, Megan Dean, Joy Kassel, Rachel Ferreira, Elise A. van den Born, Margreet Nieuwenhuis, Edward E. S. Rehmann, Holger Terheggen-Lagro, Suzanne W. J. van Karnebeek, Clara D. M. Fuchs, Sabine A. Genet Med Brief Communication PURPOSE: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities. METHODS: In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments. RESULTS: Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (P(LARS) and P(FARSB)), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2–2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency. CONCLUSION: For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation. Nature Publishing Group US 2021-06-30 2021 /pmc/articles/PMC8244667/ /pubmed/34194004 http://dx.doi.org/10.1038/s41436-021-01249-z Text en © The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics 2021 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Brief Communication Kok, Gautam Tseng, Laura Schene, Imre F. Dijsselhof, Monique E. Salomons, Gajja Mendes, Marisa I. Smith, Desiree E. C. Wiedemann, Arnaud Canton, Marie Feillet, François de Koning, Tom J. Boothe, Megan Dean, Joy Kassel, Rachel Ferreira, Elise A. van den Born, Margreet Nieuwenhuis, Edward E. S. Rehmann, Holger Terheggen-Lagro, Suzanne W. J. van Karnebeek, Clara D. M. Fuchs, Sabine A. Treatment of ARS deficiencies with specific amino acids |
title | Treatment of ARS deficiencies with specific amino acids |
title_full | Treatment of ARS deficiencies with specific amino acids |
title_fullStr | Treatment of ARS deficiencies with specific amino acids |
title_full_unstemmed | Treatment of ARS deficiencies with specific amino acids |
title_short | Treatment of ARS deficiencies with specific amino acids |
title_sort | treatment of ars deficiencies with specific amino acids |
topic | Brief Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244667/ https://www.ncbi.nlm.nih.gov/pubmed/34194004 http://dx.doi.org/10.1038/s41436-021-01249-z |
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