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Significance Aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are ubiquitously expressed enzymes catalyzing the charging of tRNAs with their cognate amino acids to provide key building blocks for protein synthesis. Currently, aaRSs represent the largest family of proteins implicated in the etiology of neurodegenerative Charcot–Marie–Tooth (CMT) disease. Using an assay that enables detection of aminoacylation within the human cell environment, this work investigates charged tRNA in CMT disease patients. The results suggest histidyl-tRNA synthetase (HisRS)–linked CMT disease is not caused by a loss-of-function mechanism. Further biochemical and biophysical analyses of several CMT disease-linked mutant HisRS proteins go on to show that disease severity is correlated with the degree of mutation-induced structural opening, thus consistent with a conformation-driven gain-of-function mechanism.

CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells