PXD067079

PXD067079 is an original dataset announced via ProteomeXchange.

Title	Phenotypic rescue of a novel heterozygous HARS L400F variant associated with Charcot-Marie-Tooth disease
Description	Cytoplasmic histidyl-tRNA synthetase (HARS1) is an essential protein in translation ligating histidine to its cognate tRNAHis. HARS1 is one of several aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth Disease, an axonal peripheral neuropathy. Advances in genetic testing identify many variants of uncertain significance. We characterize a novel heterozygous allele in HARS1, c.1200G>T (pLeu400Phe) with a familial inheritance pattern of peripheral neuropathy. Using a humanized yeast model and biochemical assays, we determined that L400F causes protein aggregation in the recombinant protein and in the humanized yeast model. L400F leads to a pronounced growth defect, especially at elevated temperatures, that persists in a heterozygous humanized yeast model, indicating a dominant negative mechanism. Cognate substrate supplementation does not ameliorate the growth defect. L400F leads to the activation of the integrated stress response (ISR) and upregulated chaperone expression in yeast. The yeast growth phenotype can be rescued by inhibition of the ISR using a specific inhibitor of the ISR activating protein general control non-depressible 2 (GCN2).
HostingRepository	PRIDE
AnnounceDate	2026-03-02
AnnouncementXML	Submission_2026-03-01_16:29:34.131.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD067079
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Kyle Hoffman
SpeciesList	scientific name: Saccharomyces cerevisiae (Baker's yeast); NCBI TaxID: NEWT:4932;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-07 10:54:19	ID requested
⏵ 1	2026-03-01 16:29:35	announced

10.1093/narmme/ugag013;

Mahmood M, Wilhelm SDP, Mendes MI, Smith DE, Kenana R, Hoffman K, Moresco AA, Siu VM, Heinemann IU, Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease. NAR Mol Med, 3(1):ugag013(2026) [pubmed]

10.6019/PXD067079;

submitter keyword: histidyl-tRNA synthetase, protein translation, Charcot-Marie-Tooth Disease

Ilka Heinemann
contact affiliation	Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada.
contact email	iheinema@uwo.ca
lab head
Kyle Hoffman
contact affiliation	Bioinformatics Solutions Inc.
contact email	khoffman@bioinfor.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067079
     1. Label: PRIDE project
     2. Name: Phenotypic rescue of a novel heterozygous HARS L400F variant associated with Charcot-Marie-Tooth disease