title: Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid.
abstract: Binding of cellular α-dystroglycan (α-DG) to its extracellular matrix ligands is fully dependent on a unique O-mannose-linked glycan. Disrupted O-mannosylation is the hallmark of the muscular dystrophy-dystroglycanopathy (MDDG) syndromes. SLC35A1, encoding the transporter of cytidine 5'-monophosphate-sialic acid, was recently identified as MDDG candidate gene. This is surprising, since sialic acid itself is dispensable for α-DG-ligand binding. In a novel SLC35A1-deficient cell model, we demonstrated a lack of α-DG O-mannosylation, ligand binding and incorporation of sialic acids. Removal of sialic acids from HAP1 wild-type cells after incorporation or preventing sialylation during synthesis did not affect α-DG O-mannosylation or ligand binding but did affect sialylation. Lentiviral-mediated complementation with the only known disease mutation p.Q101H failed to restore deficient O-mannosylation in SLC35A1 knockout cells and partly restored sialylation. These data indicate a role for SLC35A1 in α-DG O-mannosylation that is distinct from sialic acid metabolism. In addition, human SLC35A1 deficiency can be considered as a combined disorder of α-DG O-mannosylation and sialylation, a novel variant of the MDDG syndromes.
authors.affiliation: Department of Neurology, Translational Metabolic Laboratory, Department of Laboratory Medicine, Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Moniek
authors.initials: M
authors.lastname: Riemersma
authors.affiliation: Department of Neurology, Translational Metabolic Laboratory, Department of Laboratory Medicine.
authors.forename: Julia
authors.initials: J
authors.lastname: Sandrock
authors.affiliation: Cluster for Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Boltje
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands and.
authors.forename: Christian
authors.initials: C
authors.lastname: Büll
authors.affiliation: Cluster for Molecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Torben
authors.initials: T
authors.lastname: Heise
authors.affiliation: Department of Neurology, Translational Metabolic Laboratory, Department of Laboratory Medicine.
authors.forename: Angel
authors.initials: A
authors.lastname: Ashikov
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands and.
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Neurology, Translational Metabolic Laboratory, Department of Laboratory Medicine, dirk.lefeber@radboudumc.nl.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
mesh_terms: D002460:Cell Line; D003568:Cytidine Monophosphate / Q000378:metabolism; D049030:Dystroglycans / Q000378:metabolism*; D006801:Humans; D008358:Mannose / Q000378:metabolism*; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D033704:Nucleotide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000378:metabolism*
chemical_list: D033704:Nucleotide Transport Proteins; C491081:SLC35A1 protein, human; D049030:Dystroglycans; D003568:Cytidine Monophosphate; D019158:N-Acetylneuraminic Acid; D008358:Mannose