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

University of Georgia, United States
University of Iowa, United States
Mount Sinai Hospital, Canada
University of Toronto, Canada
Blizard Institute, United Kingdom
University of California, Los Angeles, United States
Wellcome Trust Sanger Institute, United Kingdom

Research Article Apr 29, 2016

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Cite this article as: eLife 2016;5:e14473 doi: 10.7554/eLife.14473

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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.

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Author details

Jeremy L Praissman

Complex Carbohydrate Research Center, University of Georgia, Athens, United States

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The authors declare that no competing interests exist.
Tobias Willer

Department of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States

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The authors declare that no competing interests exist.
M Osman Sheikh

Complex Carbohydrate Research Center, University of Georgia, Athens, United States

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The authors declare that no competing interests exist.
Ants Toi

Department of Medical Imaging, Mount Sinai Hospital, Toronto, Canada

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David Chitayat

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Canada

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Yung-Yao Lin

Blizard Institute, London, United Kingdom

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Hane Lee

Department of Human Genetics, Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

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Stephanie H Stalnaker

Complex Carbohydrate Research Center, University of Georgia, Athens, United States

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Shuo Wang

Complex Carbohydrate Research Center, University of Georgia, Athens, United States

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Pradeep Kumar Prabhakar

Complex Carbohydrate Research Center, University of Georgia, Athens, United States

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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

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The authors declare that no competing interests exist.
Derek L Stemple

Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, United Kingdom

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Steven A Moore

Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States

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The authors declare that no competing interests exist.
Kelley W Moremen

Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States

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The authors declare that no competing interests exist.
Kevin P Campbell

Department of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States

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Lance Wells

Complex Carbohydrate Research Center, University of Georgia, Athens, United States

For correspondence
lwells@ccrc.uga.edu

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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

Amy J Wagers, Harvard University, United States

Publication history

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

Copyright

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.