1. Biochemistry and Chemical Biology
  2. Human Biology and Medicine
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The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition

  1. Jeremy L Praissman
  2. Tobias Willer
  3. M Osman Sheikh
  4. Ants Toi
  5. David Chitayat
  6. Yung-Yao Lin
  7. Hane Lee
  8. Stephanie H Stalnaker
  9. Shuo Wang
  10. Pradeep Kumar Prabhakar
  11. Stanley F Nelson
  12. Derek L Stemple
  13. Steven A Moore
  14. Kelley W Moremen
  15. Kevin P Campbell
  16. Lance Wells  Is a corresponding author
  1. University of Georgia, United States
  2. University of Iowa, United States
  3. Mount Sinai Hospital, Canada
  4. University of Toronto, Canada
  5. Blizard Institute, United Kingdom
  6. University of California, Los Angeles, United States
  7. Wellcome Trust Sanger Institute, United Kingdom
Research Article
  • Cited 51
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Cite this article as: eLife 2016;5:e14473 doi: 10.7554/eLife.14473

Abstract

Multiple glycosyltransferases are essential for the proper modification of alpha-dystroglycan, as mutations in the encoding genes cause congenital/limb-girdle muscular dystrophies. Here we elucidate further the structure of an O-mannose-initiated glycan on alpha-dystroglycan that is required to generate its extracellular matrix-binding polysaccharide. This functional glycan contains a novel ribitol structure that links a phosphotrisaccharide to xylose. ISPD is a CDP-ribitol (ribose) pyrophosphorylase that generates the reduced sugar nucleotide for the insertion of ribitol in a phosphodiester linkage to the glycoprotein. TMEM5 is a UDP-xylosyl transferase that elaborates the structure. We demonstrate in a zebrafish model as well as in a human patient that defects in TMEM5 result in muscular dystrophy in combination with abnormal brain development. Thus, we propose a novel structure - a ribitol in a phosphodiester linkage - for the moiety on which TMEM5, B4GAT1, and LARGE act to generate the functional receptor for ECM proteins having LG domains.

Article and author information

Author details

  1. Jeremy L Praissman

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tobias Willer

    Department of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. M Osman Sheikh

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ants Toi

    Department of Medical Imaging, Mount Sinai Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. David Chitayat

    Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Yung-Yao Lin

    Blizard Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Hane Lee

    Department of Human Genetics, Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Stephanie H Stalnaker

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Shuo Wang

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Pradeep Kumar Prabhakar

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Stanley F Nelson

    Department of Human Genetics, Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Derek L Stemple

    Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Steven A Moore

    Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kelley W Moremen

    Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Kevin P Campbell

    Department of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Lance Wells

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    For correspondence
    lwells@ccrc.uga.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: Informed consent and ethical approval is detailed in the Materials and Methods section. All tissues and patient cells were obtained and tested according to the guidelines set out by the Human Subjects Institutional Review Board of the University of Iowa; informed consent was obtained from all subjects or their legal guardians.

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: January 16, 2016
  2. Accepted: April 28, 2016
  3. Accepted Manuscript published: April 29, 2016 (version 1)
  4. Version of Record published: June 28, 2016 (version 2)
  5. Version of Record updated: July 1, 2016 (version 3)

Copyright

© 2016, Praissman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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