AI Article Synopsis
- Heterozygous pathogenic variants in the HARS gene are linked to Charcot-Marie-Tooth (CMT) type 2W disease, a form of peripheral neuropathy, with at least 60 variants identified across several aminoacyl-tRNA synthetases.
- A novel HARS variant, c.412T>C; p.Y138H, was discovered in a patient using a CMT gene panel, prompting further investigation into its effects.
- Through studies using a humanized yeast model and protein analysis, researchers found that the p.Y138H variant caused protein dimerization issues and growth defects, but these problems showed improvement when histidine was supplied, suggesting a possible avenue for clinical trials.
Article Abstract
Heterozygous pathogenic variants in the histidyl-tRNA synthetase (HARS) gene are associated with Charcot-Marie-Tooth (CMT) type 2W disease, classified as an axonal peripheral neuropathy. To date, at least 60 variants causing CMT symptoms have been identified in seven different aminoacyl-tRNA synthetases, with eight being found in the catalytic domain of HARS. The genetic data clearly show a causative role of aminoacyl-tRNA synthetases in CMT; however, the cellular mechanisms leading to pathology can vary widely and are unknown in the case of most identified variants. Here we describe a novel HARS variant, c.412T>C; p.Y138H, identified through a CMT gene panel in a patient with peripheral neuropathy. To determine the effect of p.Y138H we employed a humanized HARS yeast model and recombinant protein biochemistry, which identified a deficiency in protein dimerization and a growth defect which shows mild but significant improvement with histidine supplementation. This raises the potential for a clinical trial of histidine.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580374 | PMC |
| http://dx.doi.org/10.1002/iub.2918 | DOI Listing |
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