title: The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition.
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.
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Praissman
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.|Howard Hughes Medical Institute, University of Iowa, Iowa City, United States.|Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, United States.|Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States.
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.
authors.forename: M Osman
authors.identifier: 0000-0002-9481-8318
authors.initials: MO
authors.lastname: Sheikh
authors.affiliation: Department of Medical Imaging, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Ants
authors.initials: A
authors.lastname: Toi
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.|The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Canada.|Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: Blizard Institute, London, United Kingdom.|Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.|Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Yung-Yao
authors.identifier: 0000-0002-0435-7694
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.|David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.|Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Stalnaker
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Prabhakar
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.|David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.|Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, United States.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.|Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States.
authors.forename: Kelley W
authors.initials: KW
authors.lastname: Moremen
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, United States.|Howard Hughes Medical Institute, University of Iowa, Iowa City, United States.|Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, United States.|Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, United States.
authors.forename: Kevin P
authors.identifier: 0000-0003-2066-5889
authors.initials: KP
authors.lastname: Campbell
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, United States.|Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States.
authors.forename: Lance
authors.identifier: 0000-0003-4956-5363
authors.initials: L
authors.lastname: Wells
mesh_terms: D000818:Animals; D049030:Dystroglycans / Q000737:chemistry* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D008358:Mannose / Q000032:analysis; D008565:Membrane Proteins / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism; D010430:Pentosyltransferases; D011134:Polysaccharides / Q000032:analysis*; D011485:Protein Binding; D012255:Ribitol / Q000032:analysis; D015027:Zebrafish
chemical_list: C483081:DAG1 protein, human; D008565:Membrane Proteins; D011134:Polysaccharides; D049030:Dystroglycans; D012255:Ribitol; D010430:Pentosyltransferases; C578283:RXYLT1 protein, human; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human; D008358:Mannose
keywords: O-mannosylation; alpha-dystroglycan; biochemistry; congenital muscular dystrophy; glycosylation; human; human biology; mass spectrometry; medicine; ribitol; zebrafish