Missense mutations in beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome
Publication year
2013Source
Human Molecular Genetics, 22, 9, (2013), pp. 1746-54ISSN
Publication type
Article / Letter to editor

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Organization
Human Genetics
Neurology
Laboratory of Genetic, Endocrine and Metabolic Diseases
Journal title
Human Molecular Genetics
Volume
vol. 22
Issue
iss. 9
Page start
p. 1746
Page end
p. 54
Subject
DCN MP - Plasticity and memory; DCN NN - Brain networks and neuronal communication; DCN PAC - Perception action and control IGMD 4: Glycostation disorders; IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 4: Glycostation disorders; NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 9: Renal disorderAbstract
Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (alphaDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective alphaDG glycosylation and reduced ligand binding by alphaDG causing a clinically heterogeneous group of congenital muscular dystrophies, commonly referred to as dystroglycanopathies. The most severe clinical form, Walker-Warburg syndrome (WWS), is characterized by congenital muscular dystrophy and severe neurological and ophthalmological defects. Here, we report two homozygous missense mutations in the beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) gene in a family affected with WWS. Functional studies confirmed the pathogenicity of the mutations. First, expression of wild-type but not mutant B3GNT1 in human prostate cancer (PC3) cells led to increased levels of alphaDG glycosylation. Second, morpholino knockdown of the zebrafish b3gnt1 orthologue caused characteristic muscular defects and reduced alphaDG glycosylation. These functional studies identify an important role of B3GNT1 in the synthesis of the uncharacterized laminin-binding glycan of alphaDG and implicate B3GNT1 as a novel causative gene for WWS.
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- Faculty of Medical Sciences [86204]
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