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Towards a Cure for HARS Disease

Histidyl-tRNA synthetase (HARS) ligates histidine to its cognate transfer RNA (tRNA(His)). Mutations in HARS cause the human genetic disorders Usher syndrome type 3B (USH3B) and Charcot-Marie-Tooth syndrome type 2W (CMT2W). Treatment for these diseases remains symptomatic, and no disease specific tr...

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Autores principales: Wilhelm, Sarah D. P., Kenana, Rosan, Qiu, Yi, O’Donoghue, Patrick, Heinemann, Ilka U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956352/
https://www.ncbi.nlm.nih.gov/pubmed/36833180
http://dx.doi.org/10.3390/genes14020254
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author Wilhelm, Sarah D. P.
Kenana, Rosan
Qiu, Yi
O’Donoghue, Patrick
Heinemann, Ilka U.
author_facet Wilhelm, Sarah D. P.
Kenana, Rosan
Qiu, Yi
O’Donoghue, Patrick
Heinemann, Ilka U.
author_sort Wilhelm, Sarah D. P.
collection PubMed
description Histidyl-tRNA synthetase (HARS) ligates histidine to its cognate transfer RNA (tRNA(His)). Mutations in HARS cause the human genetic disorders Usher syndrome type 3B (USH3B) and Charcot-Marie-Tooth syndrome type 2W (CMT2W). Treatment for these diseases remains symptomatic, and no disease specific treatments are currently available. Mutations in HARS can lead to destabilization of the enzyme, reduced aminoacylation, and decreased histidine incorporation into the proteome. Other mutations lead to a toxic gain-of-function and mistranslation of non-cognate amino acids in response to histidine codons, which can be rescued by histidine supplementation in vitro. We discuss recent advances in characterizing HARS mutations and potential applications of amino acid and tRNA therapy for future gene and allele specific therapy.
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spelling pubmed-99563522023-02-25 Towards a Cure for HARS Disease Wilhelm, Sarah D. P. Kenana, Rosan Qiu, Yi O’Donoghue, Patrick Heinemann, Ilka U. Genes (Basel) Review Histidyl-tRNA synthetase (HARS) ligates histidine to its cognate transfer RNA (tRNA(His)). Mutations in HARS cause the human genetic disorders Usher syndrome type 3B (USH3B) and Charcot-Marie-Tooth syndrome type 2W (CMT2W). Treatment for these diseases remains symptomatic, and no disease specific treatments are currently available. Mutations in HARS can lead to destabilization of the enzyme, reduced aminoacylation, and decreased histidine incorporation into the proteome. Other mutations lead to a toxic gain-of-function and mistranslation of non-cognate amino acids in response to histidine codons, which can be rescued by histidine supplementation in vitro. We discuss recent advances in characterizing HARS mutations and potential applications of amino acid and tRNA therapy for future gene and allele specific therapy. MDPI 2023-01-18 /pmc/articles/PMC9956352/ /pubmed/36833180 http://dx.doi.org/10.3390/genes14020254 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Wilhelm, Sarah D. P.
Kenana, Rosan
Qiu, Yi
O’Donoghue, Patrick
Heinemann, Ilka U.
Towards a Cure for HARS Disease
title Towards a Cure for HARS Disease
title_full Towards a Cure for HARS Disease
title_fullStr Towards a Cure for HARS Disease
title_full_unstemmed Towards a Cure for HARS Disease
title_short Towards a Cure for HARS Disease
title_sort towards a cure for hars disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956352/
https://www.ncbi.nlm.nih.gov/pubmed/36833180
http://dx.doi.org/10.3390/genes14020254
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