Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Human Molecular Genetics |
Volume | 24 |
Issue number | 8 |
Pages (from-to) | 2241-6 |
Number of pages | 6 |
ISSN | 0964-6906 |
DOIs | |
Publication status | Published - 15 Apr 2015 |
Externally published | Yes |
- Cell Line, Cytidine Monophosphate/metabolism, Dystroglycans/metabolism, Humans, Mannose/metabolism, Mutation, N-Acetylneuraminic Acid/metabolism, Nucleotide Transport Proteins/genetics, Walker-Warburg Syndrome/genetics
Research areas
ID: 201898313