Treatment of ARS deficiencies with specific amino acids.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
18
03
2021
accepted:
08
06
2021
revised:
07
06
2021
pubmed:
2
7
2021
medline:
12
11
2021
entrez:
1
7
2021
Statut:
ppublish
Résumé
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. 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. Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (P 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.
Identifiants
pubmed: 34194004
doi: 10.1038/s41436-021-01249-z
pii: S1098-3600(21)05175-3
pmc: PMC8244667
doi:
Substances chimiques
Amino Acids
0
RNA, Transfer
9014-25-9
Amino Acyl-tRNA Synthetases
EC 6.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2202-2207Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
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