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Treatment of ARS de...
Treatment of ARS deficiencies with specific amino acids
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- Kok, Gautam (author)
- University Medical Center Utrecht
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- Tseng, Laura (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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- Schene, Imre F. (author)
- University Medical Center Utrecht
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- Dijsselhof, Monique E. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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- Salomons, Gajja (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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- Mendes, Marisa I. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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- Smith, Desiree E.C. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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- Wiedemann, Arnaud (author)
- University Hospital of Nancy
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- Canton, Marie (author)
- University Hospital of Nancy
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- Feillet, François (author)
- University Hospital of Nancy
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- de Koning, Tom J. (author)
- Lund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,University of Groningen
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- Boothe, Megan (author)
- University of Florida
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- Dean, Joy (author)
- University of Florida
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- Kassel, Rachel (author)
- University of Alabama
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- Ferreira, Elise A. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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van den Born, Margreet (author)
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- Nieuwenhuis, Edward E.S. (author)
- University Medical Center Utrecht
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- Rehmann, Holger (author)
- Flensburg University of Applied Sciences
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- Terheggen-Lagro, Suzanne W.J. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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- van Karnebeek, Clara D.M. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam,Radboud University Medical Center
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- Fuchs, Sabine A. (author)
- Amsterdam UMC - Vrije Universiteit Amsterdam
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(creator_code:org_t)
- Elsevier BV, 2021
- 2021
- English.
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 23:11, s. 2202-2207
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Kok, Gautam
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Tseng, Laura
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Schene, Imre F.
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Dijsselhof, Moni ...
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Salomons, Gajja
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Mendes, Marisa I ...
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show more...
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Smith, Desiree E ...
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Wiedemann, Arnau ...
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Canton, Marie
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Feillet, Françoi ...
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de Koning, Tom J ...
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Boothe, Megan
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Dean, Joy
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Kassel, Rachel
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Ferreira, Elise ...
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van den Born, Ma ...
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Nieuwenhuis, Edw ...
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Rehmann, Holger
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Terheggen-Lagro, ...
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van Karnebeek, C ...
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Fuchs, Sabine A.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Microbiology in ...
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Genetics in Medi ...
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Lund University