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Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy.

  • Abbott, Jamie A1
  • Meyer-Schuman, Rebecca2
  • Lupo, Vincenzo3
  • Feely, Shawna4
  • Mademan, Inès5, 6
  • Oprescu, Stephanie N2
  • Griffin, Laurie B7, 8
  • Alberti, M Antonia9
  • Casasnovas, Carlos9
  • Aharoni, Sharon10
  • Basel-Vanagaite, Lina11, 12, 13, 14
  • Züchner, Stephan15
  • De Jonghe, Peter5, 6, 16
  • Baets, Jonathan5, 6, 16
  • Shy, Michael E4
  • Espinós, Carmen3
  • Demeler, Borries17
  • Antonellis, Anthony2, 7
  • Francklyn, Christopher1
  • 1 Department of Biochemistry, College of Medicine, University of Vermont, Burlington, Vermont.
  • 2 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
  • 3 Unit of Genetics and Genomics of Neuromuscular Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. , (Spain)
  • 4 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
  • 5 Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium. , (Belgium)
  • 6 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium. , (Belgium)
  • 7 Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, Michigan.
  • 8 Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, Michigan.
  • 9 Department of Neurology, Hospital Universitario de Bellvitge, Barcelona, Spain. , (Spain)
  • 10 Institute of Child Neurology, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Tel Aviv, Israel. , (Israel)
  • 11 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. , (Israel)
  • 12 Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. , (Israel)
  • 13 Pediatric Genetics Unit, Schneider Children's Medical Center, Petah Tikva, Israel. , (Israel)
  • 14 Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel. , (Israel)
  • 15 Dr John T McDonald Foundation Department of Human Genetics & John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida.
  • 16 Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium. , (Belgium)
  • 17 Department of Biochemistry, The University of Texas Health Sciences at San Antonio, San Antonio, Texas.
Published Article
Human Mutation
Wiley (John Wiley & Sons)
Publication Date
Mar 01, 2018
DOI: 10.1002/humu.23380
PMID: 29235198


Histidyl-tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot-Marie-Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W-linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild-type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT-associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology. © 2017 Wiley Periodicals, Inc.

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