SUMMARY:
s. V133F proteins displayed reduced thermal stability in vitro, which was rescued by tRNA.
TITLE:
Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model
DESCRIPTION:
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations V133F, V155G, Y330C, S356N in the HARS catalytic domain cause Charcot Marie Tooth Disease Type 2 W (CMT2W), while RNA-binding domain mutation Y454S causes recessive Usher Syndrome Type IIIB (USH3B). In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog…
CONTENT:
Hum Mol Genet. 2022 Sep 26:ddac239. doi: 10.1093/hmg/ddac239. Online ahead of print.
ABSTRACT
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations V133F, V155G, Y330C, S356N in the HARS catalytic domain cause Charcot Marie Tooth Disease Type 2 W (CMT2W), while RNA-binding domain mutation Y454S causes recessive Usher Syndrome Type IIIB (USH3B). In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog hts1 at high expression levels. CMT2W associated mutations, but not Y454S, resulted in reduced growth. We show mistranslation of histidine to glutamine and threonine in V155G and S356N but not Y330C mutants in yeast. Mistranslating V155G and S356N mutants lead to accumulation of insoluble proteins, which was rescued by histidine. Mutants V133F and Y330C showed the most significant growth defect and decreased HARS abundance in cells. Here, histidine supplementation led to insoluble protein aggregation and further reduced viability, indicating histidine toxicity associated with these mutants. V133F proteins displayed reduced thermal stability in vitro, which was rescued by tRNA. Our data will inform future treatment options for HARS patients, where histidine supplementation may either have a toxic or compensating effect depending on the nature of the causative HARS variant.
PMID:36164730 | DOI:10.1093/hmg/ddac239
SOURCE:
Human molecular genetics
TAGS:
s V133F
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-09-27T06:48:20Z
DATE – DOI: 2022-09-27T06:48:20Z
DATE – PUBMED: 2022 Sep 26
DATE OUTPUT MATCHED: True
DATE – ADDED:
Tue, 27 Sep 2022 06:00:00 -0400
DATE – RETRIEVED:
09/27/22 06:59AM
2022-09-27T06:59:19-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:36164730,doi:10.1093/hmg/ddac239
PUBMED ID:
pubmed:36164730
DOI:
10.1093/hmg/ddac239
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36164730/
LINK – DOI:
https://doi.org/10.1093/hmg/ddac239
LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac239/6717848
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-27T06:59:19-04:00, https://www.cmttreatmentreport.com.
