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

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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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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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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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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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Kelley W Moremen

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

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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.

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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.