Treatment of ARS deficiencies with specific amino acids

Autor: Monique E. Dijsselhof, Tom J. de Koning, Laura A. Tseng, Edward E. S. Nieuwenhuis, Elise A. Ferreira, Rachel Kassel, Margreet van den Born, Holger Rehmann, Sabine A. Fuchs, Gautam Kok, Imre F. Schene, Marie Canton, Suzanne W J Terheggen-Lagro, Arnaud Wiedemann, Joy Dean, Desiree E.C. Smith, Megan Boothe, Clara D.M. van Karnebeek, Gajja Salomons, François Feillet, Marisa I. Mendes
Přispěvatelé: Graduate School, Paediatrics, ANS - Cellular & Molecular Mechanisms, ANS - Compulsivity, Impulsivity & Attention, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, AGEM - Inborn errors of metabolism, ANS - Amsterdam Neuroscience, Paediatric Pulmonology, Laboratory Medicine, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), AGEM - Endocrinology, metabolism and nutrition, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pediatrics, Movement Disorder (MD)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Genetics in Medicine
Genetics in medicine, 23(11), 2202-2207. Lippincott Williams and Wilkins
Kok, G, Tseng, L, Schene, I F, Dijsselhof, M E, Salomons, G, Mendes, M I, Smith, D E C, Wiedemann, A, Canton, M, Feillet, F, de Koning, T J, Boothe, M, Dean, J, Kassel, R, Ferreira, E A, van den Born, M, Nieuwenhuis, E E S, Rehmann, H, Terheggen-Lagro, S W J, van Karnebeek, C D M & Fuchs, S A 2021, ' Treatment of ARS deficiencies with specific amino acids ', Genetics in Medicine, vol. 23, no. 11, pp. 2202-2207 . https://doi.org/10.1038/s41436-021-01249-z
Genetics in Medicine, 23(11), 2202-2207. Lippincott Williams and Wilkins
Genetics in Medicine, 23(11), 2202-2207. Nature Publishing Group
ISSN: 1530-0366
1098-3600
DOI: 10.1038/s41436-021-01249-z
Popis: 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.
Databáze: OpenAIRE
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