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Elife. 2016 Apr 29;5. pii: e14473. doi: 10.7554/eLife.14473.

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

Author information

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.

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

PMID:
27130732
PMCID:
PMC4924997
DOI:
10.7554/eLife.14473
[Indexed for MEDLINE]
Free PMC Article

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