Characterization of a novel heterozygous variant in the histidyl-tRNA synthetase gene associated with Charcot-Marie-Tooth disease type 2W.

Autor: Wilhelm SDP; Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada., Moresco AA; Division of Medical Genetics, Department of Paediatrics, The University of Western Ontario, London, Ontario, Canada., Rivero AD; Institute for Neurological Research (FLENI), Buenos Aires, Argentina., Siu VM; Division of Medical Genetics, Department of Paediatrics, The University of Western Ontario, London, Ontario, Canada.; Children's Health Research Institute, London, Ontario, Canada., Heinemann IU; Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada.; Children's Health Research Institute, London, Ontario, Canada.
Jazyk: angličtina
Zdroj: IUBMB life [IUBMB Life] 2024 Dec; Vol. 76 (12), pp. 1125-1138. Date of Electronic Publication: 2024 Oct 01.
DOI: 10.1002/iub.2918
Abstrakt: 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.
(© 2024 The Author(s). IUBMB Life published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)
Databáze: MEDLINE
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