Histidine supplementation can escalate or rescue HARS deficiency in a Charcot–Marie–Tooth disease model

• DOI: 10.1093/hmg/ddac239
• Publication Date: 2022-09-27T06:48:19Z
• Authors: Yi Qiu; Rosan Kenana; Aruun Beharry; Sarah D P Wilhelm; Sung Yuan Hsu; Victoria M Siu; Martin Duennwald; Ilka U Heinemann
• Keywords: Wild type

Abstract Aminoacyl-tRNA synthetases 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 and S356N in the HARS catalytic domain cause Charcot–Marie–Tooth disease type 2 W (CMT2W), while tRNA-binding mutation Y454S causes recessive Usher syndrome IIIB. a yeast model, all human variants complemented genomic deletion of ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, resulted reduced growth. We show mistranslation histidine to glutamine threonine V155G mutants yeast. Mistranslating lead accumulation insoluble proteins, which was rescued by histidine. Mutants V133F showed most significant growth defect decreased abundance cells. Here, supplementation led aggregation further viability, indicating toxicity with these mutants. proteins displayed thermal stability vitro, tRNA. Our data will inform future treatment options patients, where may either have toxic or compensating effect depending on nature causative variant.