PXD034865

PXD034865 is an original dataset announced via ProteomeXchange.

Title	Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model
Description	Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis¬. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations in the HARS catalytic domain are associated with Charcot Marie Tooth Disease Type 2W (CMT2W), while anticodon-binding domain mutations cause Usher Syndrome Type IIIB (USH3B). We use yeast as a model system to study disease-causing HARS mutations (V133F, V155G, Y330C, S356N) associated with CMT2W, and Y454S, associated with USH3B. All human HARS variants complemented genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, result in reduced growth. HARS V155G and S356N cause accumulation of insoluble proteins and mistranslation in yeast, and the growth defect of these mutants was rescued by histidine addition to the growth media, restoring the soluble proteome. V133F and Y330C, on the other hand, lead to decreased HARS abundance. Histidine supplementation further reduced viability in yeast expressing V133F and Y330C, and lead to insoluble protein accumulation, indicating histidine toxicity associated with these mutants. Because histidine is in clinical trials as treatment for USH3B, our data will inform future treatment options for these as well as CMT patients, where histidine supplementation may either have a toxic or compensating effect dependingon the nature of the causative HARS variant.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:33:34.582.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD034865
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Yi Qiu
SpeciesList	scientific name: Saccharomyces cerevisiae (Baker's yeast); NCBI TaxID: 4932;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-24 08:31:40	ID requested
1	2023-03-10 12:50:29	announced
⏵ 2	2023-11-14 07:33:38	announced	2023-11-14: Updated project metadata.

10.6019/PXD034865;

Qiu Y, Kenana R, Beharry A, Wilhelm SDP, Hsu SY, Siu VM, Duennwald M, Heinemann IU, Histidine supplementation can escalate or rescue HARS deficiency in a Charcot-Marie-Tooth disease model. Hum Mol Genet, 32(5):810-824(2023) [pubmed]

submitter keyword: histidyl-tRNA synthetase (HARS), transfer RNA, genetic disease, proteome, protein synthesis

Ilka U. Heinemann
contact affiliation	University of Western Ontario, Canada, Department of Biochemistry
contact email	iheinema@uwo.ca
lab head
Yi Qiu
contact affiliation	Western University
contact email	yqiu93@uwo.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034865
     1. Label: PRIDE project
     2. Name: Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model