Treatment of ARS deficiencies with specific amino acids
(2021) In Genetics in Medicine 23(11). p.2202-2207- Abstract
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... (More)
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 (PLARS and PFARSB), 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.
(Less)
- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Genetics in Medicine
- volume
- 23
- issue
- 11
- pages
- 2202 - 2207
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:34194004
- scopus:85108909862
- ISSN
- 1098-3600
- DOI
- 10.1038/s41436-021-01249-z
- language
- English
- LU publication?
- yes
- id
- 2dd106b2-8955-4f80-9a69-1914ddeac406
- date added to LUP
- 2021-07-12 08:39:13
- date last changed
- 2024-06-29 14:28:11
@article{2dd106b2-8955-4f80-9a69-1914ddeac406,
abstract = {{<p>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<sup>LARS</sup> and P<sup>FARSB</sup>), 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.</p>}},
author = {{Kok, Gautam and Tseng, Laura and Schene, Imre F. and Dijsselhof, Monique E. and Salomons, Gajja and Mendes, Marisa I. and Smith, Desiree E.C. and Wiedemann, Arnaud and Canton, Marie and Feillet, François and de Koning, Tom J. and Boothe, Megan and Dean, Joy and Kassel, Rachel and Ferreira, Elise A. and van den Born, Margreet and Nieuwenhuis, Edward E.S. and Rehmann, Holger and Terheggen-Lagro, Suzanne W.J. and van Karnebeek, Clara D.M. and Fuchs, Sabine A.}},
issn = {{1098-3600}},
language = {{eng}},
number = {{11}},
pages = {{2202--2207}},
publisher = {{Nature Publishing Group}},
series = {{Genetics in Medicine}},
title = {{Treatment of ARS deficiencies with specific amino acids}},
url = {{http://dx.doi.org/10.1038/s41436-021-01249-z}},
doi = {{10.1038/s41436-021-01249-z}},
volume = {{23}},
year = {{2021}},
}