2. Academic Validation
  3. The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition

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

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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