Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

TISSUE(S): Haploid Cell

DISEASE(S): Charcot-marie-tooth Disease

SUBMITTER: Yi Qiu

LAB HEAD: Ilka U. Heinemann

PROVIDER: PXD034865 | Pride | 2023-03-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2022_042_2021_035_contam.fasta	Fasta
	peptides_1_1_0_S356N.mzid.gz	Mzid
	peptides_1_1_0_V155G.mzid.gz	Mzid
	peptides_1_1_0_WT.mzid.gz	Mzid
	peptides_1_1_0_Y330C.mzid.gz	Mzid

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Publications

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

Qiu Yi Y Kenana Rosan R Beharry Aruun A Wilhelm Sarah D P SDP Hsu Sung Yuan SY Siu Victoria M VM Duennwald Martin M Heinemann Ilka U IU

Human molecular genetics 20230201 5

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 domain mutation Y454S causes recessive Usher syndrome type IIIB. In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog HTS1 at high ...[more]

PMID: 36164730

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