The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition

  • Elife. 2016 Apr 29;5:e14473. doi: 10.7554/eLife.14473.
Jeremy L Praissman  1 ,  Tobias Willer  2  3  4  5 ,  M Osman Sheikh  1 ,  Ants Toi  6 ,  David Chitayat  7  8  9 ,  Yung-Yao Lin  10  11  12 ,  Hane Lee  13  14  15 ,  Stephanie H Stalnaker  1 ,  Shuo Wang  1 ,  Pradeep Kumar Prabhakar  1 ,  Stanley F Nelson  13  14  15 ,  Derek L Stemple  12 ,  Steven A Moore  16 ,  Kelley W Moremen  1  17 ,  Kevin P Campbell  2  3  4  5 ,  Lance Wells  1  17
Affiliations
  • 1. Complex Carbohydrate Research Center, University of Georgia, Athens, United States.
  • 2. Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.
  • 3. Howard Hughes Medical Institute, University of Iowa, Iowa City, United States.
  • 4. Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, United States.
  • 5. Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States.
  • 6. Department of Medical Imaging, Mount Sinai Hospital, Toronto, Canada.
  • 7. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
  • 8. The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Canada.
  • 9. Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada.
  • 10. Blizard Institute, London, United Kingdom.
  • 11. Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • 12. Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
  • 13. Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.
  • 14. David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
  • 15. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States.
  • 16. Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, United States.
  • 17. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States.
PMID: 27130732 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.

Keywords
O-mannosylation; alpha-dystroglycan; biochemistry; congenital muscular dystrophy; glycosylation; human; human biology; mass spectrometry; medicine; ribitol; zebrafish.
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