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

Authors

  • Aimée Vester,

    1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan
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  • Gisselle Velez-Ruiz,

    1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
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  • Heather M. McLaughlin,

    1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan
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  • NISC Comparative Sequencing Program,

    1. NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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  • James R. Lupski,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Department of Pediatrics, Baylor College of Medicine, Houston, Texas
    3. Genetics, Texas Children's Hospital, Houston, Texas
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  • Kevin Talbot,

    1. Department of Clinical Neurology, University of Oxford, Oxford, United Kingdom
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  • Jeffery M. Vance,

    1. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
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  • Stephan Züchner,

    1. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
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  • Ricardo H. Roda,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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  • Kenneth H. Fischbeck,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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  • Leslie G. Biesecker,

    1. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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  • Garth Nicholson,

    1. Northcott Neuroscience Laboratory, ANZAC Research Institute and Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia
    2. Faculty of Medicine, University of Sydney, Camperdown, New South Wales, Australia
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  • Asim A. Beg,

    Corresponding author
    1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan
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  • Anthony Antonellis

    Corresponding author
    1. Departments of Neurology, University of Michigan Medical School, Ann Arbor, Michigan
    • Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan
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  • Communicated by Ming Qi

  • Contract Grant Sponsor: National Institute of Neurological Diseases and Stroke (grants NS060983 to A.A., R01NS052767 to S.Z., and U54NS065712 to S.Z.); Intramural Research Programs of the National Human Genome Research Institute and National Institute of Neurological Diseases and Stroke (National Institutes of Health).

Correspondence to: Anthony Antonellis, University of Michigan Medical School, 3710A Medical Sciences II, 1241 E. Catherine St. SPC 5618, Ann Arbor, MI 48109. E-mail: antonell@umich.edu or Asim A. Beg, University of Michigan Medical School, 1301D MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109. E-mail: asimbeg@umich.edu

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.

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