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Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth disease.
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- Additional Information
- Source:
Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
- Publication Information:
Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
- Subject Terms:
- Abstract:
Aminoacyl-tRNA synthetases are indispensable enzymes in all cells, ensuring the correct pairing of amino acids to their cognate tRNAs to maintain translation fidelity. Autosomal dominant mutations V133F and Y330C in histidyl-tRNA synthetase (HARS) cause the genetic disorder Charcot-Marie-Tooth type 2W (CMT2W). Treatments are currently restricted to symptom relief, with no therapeutic available that targets the cause of disease. We previously found that histidine supplementation alleviated phenotypic defects in a humanized yeast model of CMT2W caused by HARS V155G and S356N that also unexpectedly exacerbated the phenotype of the two HARS mutants V133F and Y330C. Here, we show that V133F destabilizes recombinant HARS protein, which is rescued in the presence of tRNAHis. HARS V133F and Y330C cause mistranslation and cause changes to the proteome without activating the integrated stress response as validated by mass spectrometry and growth defects that persist with histidine supplementation. The growth defects and reduced translation fidelity caused by V133F and Y330C mutants were rescued by supplementation with human tRNAHis in a humanized yeast model. Our results demonstrate the feasibility of cognate tRNA as a therapeutic that rescues HARS deficiency and ameliorates toxic mistranslation generated by causative alleles for CMT.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Grant Information:
04776 Natural Sciences and Engineering Research Council of Canada; 232341 Canada Research Chairs; 165985 Canada CAPMC CIHR; ER-18-14-183 Ontario Ministry of Research and Innovation; Huntington Society of Canada Endowed Research Chair; Rare Disease Models and Mechanism; Canada Graduate Scholarship (Masters program); 165985 Canada CAPMC CIHR
- Accession Number:
9014-25-9 (RNA, Transfer)
EC 6.1.1.21 (Histidine-tRNA Ligase)
4QD397987E (Histidine)
- Publication Date:
Date Created: 20241112 Date Completed: 20241221 Latest Revision: 20241221
- Publication Date:
20241222
- Accession Number:
10.1093/nar/gkae996
- Accession Number:
39530218
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