Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid

TY - JOUR

T1 - Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid

AU - Riemersma, Moniek

AU - Sandrock, Julia

AU - Boltje, Thomas J

AU - Büll, Christian

AU - Heise, Torben

AU - Ashikov, Angel

AU - Adema, Gosse J

AU - van Bokhoven, Hans

AU - Lefeber, Dirk J

N1 - © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

PY - 2015/4/15

Y1 - 2015/4/15

N2 - 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.

AB - 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.

KW - Cell Line

KW - Cytidine Monophosphate/metabolism

KW - Dystroglycans/metabolism

KW - Humans

KW - Mannose/metabolism

KW - Mutation

KW - N-Acetylneuraminic Acid/metabolism

KW - Nucleotide Transport Proteins/genetics

KW - Walker-Warburg Syndrome/genetics

U2 - 10.1093/hmg/ddu742

DO - 10.1093/hmg/ddu742

M3 - Journal article

C2 - 25552652

SN - 0964-6906

VL - 24

SP - 2241

EP - 2246

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 8

ER -