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A Recurrent loss-of-function alanyl-tRNA synthetase (AARS ) mutation in patients with charcot-marie-tooth disease type 2N (CMT2N)

Authors

  • Heather M. McLaughlin,

    1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI
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  • Reiko Sakaguchi,

    1. Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, PA
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  • William Giblin,

    1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI
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  • NIH Intramural Sequencing Center,

    1. NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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  • Thomas E. Wilson,

    1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI
    2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
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  • Leslie Biesecker,

    1. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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  • James R. Lupski,

    1. Departments of Molecular and Human Genetics
    2. Pediatrics, Baylor College of Medicine, Houston, TX
    3. Texas Children's Hospital, Houston, TX
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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, FL
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  • Stephan Züchner,

    1. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
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  • Yi-Chung Lee,

    1. Department of Neurology, The Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taiwan, Republic of China
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  • Marina Kennerson,

    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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  • Ya-Ming Hou,

    1. Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, PA
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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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  • Anthony Antonellis

    Corresponding author
    1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI
    2. Department of Neurology, University of Michigan Medical School, Ann Arbor, MI
    • University of Michigan Medical School, 3710A Medical Sciences II, 1241 E. Catherine St. SPC 5618, Ann Arbor, MI 48109-5618
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Errata

This article is corrected by:

  1. Errata: A Recurrent Loss-of-Function Alanyl-tRNA Synthetase (AARS) Mutation in Patients with Charcot-Marie-Tooth Disease Type 2N (CMT2N) Volume 35, Issue 4, 512, Article first published online: 18 February 2014

  • Communicated by George P. Patrinos

Abstract

Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamination of a CpG dinucleotide gives rise to the recurrent p.Arg329His AARS mutation. Together, our data suggest that impaired tRNA charging plays a role in the molecular pathology of CMT2N, and that patients with CMT should be directly tested for the p.Arg329His AARS mutation. Hum Mutat 33:244–253, 2012. © 2011 Wiley Periodicals, Inc.

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