Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid. (30th December 2014)

• Record Type: Journal Article
• Authors: Riemersma, Moniek; Sandrock, Julia; Boltje, Thomas J.; Büll, Christian; Heise, Torben; Ashikov, Angel; Adema, Gosse J.; van Bokhoven, Hans; Lefeber, Dirk J.
• Is Part Of: Human molecular genetics. Volume 24:Number 8(2015:Apr. 15)
• Page Start: 2241
• Page End: 2246
• Publication Date: 2014-12-30
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddu742
• Languages: English
• ISSNs: 0964-6906

Abstract

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.