A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo

Aimée Vester, Gisselle Velez-Ruiz, Heather M. McLaughlin, Comparative Sequencing Program Nisc Comparative Sequencing Program, James R. Lupski, Kevin Talbot, Jeffery M Vance, Stephan L Zuchner, Ricardo H. Roda, Kenneth H. Fischbeck, Leslie G. Biesecker, Garth Nicholson, Asim A. Beg, Anthony Antonellis

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.

Original languageEnglish
Pages (from-to)191-199
Number of pages9
JournalHuman Mutation
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Histidine-tRNA Ligase
Amino Acyl-tRNA Synthetases
Peripheral Nervous System Diseases
Genes
Alleles
Exome
Phenotype
Amino Acids
Mutation
Poisons
Transfer RNA
Yeasts
Genome
Pathology
Neurons
Enzymes
Population

Keywords

  • Aminoacyl-tRNA synthetases
  • HARS
  • Neurotoxicity
  • Peripheral neuropathy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Vester, A., Velez-Ruiz, G., McLaughlin, H. M., Nisc Comparative Sequencing Program, C. S. P., Lupski, J. R., Talbot, K., ... Antonellis, A. (2013). A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo. Human Mutation, 34(1), 191-199. https://doi.org/10.1002/humu.22210

A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo. / Vester, Aimée; Velez-Ruiz, Gisselle; McLaughlin, Heather M.; Nisc Comparative Sequencing Program, Comparative Sequencing Program; Lupski, James R.; Talbot, Kevin; Vance, Jeffery M; Zuchner, Stephan L; Roda, Ricardo H.; Fischbeck, Kenneth H.; Biesecker, Leslie G.; Nicholson, Garth; Beg, Asim A.; Antonellis, Anthony.

In: Human Mutation, Vol. 34, No. 1, 01.01.2013, p. 191-199.

Research output: Contribution to journalArticle

Vester, A, Velez-Ruiz, G, McLaughlin, HM, Nisc Comparative Sequencing Program, CSP, Lupski, JR, Talbot, K, Vance, JM, Zuchner, SL, Roda, RH, Fischbeck, KH, Biesecker, LG, Nicholson, G, Beg, AA & Antonellis, A 2013, 'A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo', Human Mutation, vol. 34, no. 1, pp. 191-199. https://doi.org/10.1002/humu.22210
Vester A, Velez-Ruiz G, McLaughlin HM, Nisc Comparative Sequencing Program CSP, Lupski JR, Talbot K et al. A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo. Human Mutation. 2013 Jan 1;34(1):191-199. https://doi.org/10.1002/humu.22210
Vester, Aimée ; Velez-Ruiz, Gisselle ; McLaughlin, Heather M. ; Nisc Comparative Sequencing Program, Comparative Sequencing Program ; Lupski, James R. ; Talbot, Kevin ; Vance, Jeffery M ; Zuchner, Stephan L ; Roda, Ricardo H. ; Fischbeck, Kenneth H. ; Biesecker, Leslie G. ; Nicholson, Garth ; Beg, Asim A. ; Antonellis, Anthony. / A Loss-of-Function Variant in the Human Histidyl-tRNA Synthetase (HARS) Gene is Neurotoxic In Vivo. In: Human Mutation. 2013 ; Vol. 34, No. 1. pp. 191-199.
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