Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
Copyright policy )Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (αDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective αDG glycosylation and reduced ligand binding by αDG 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 β-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 αDG glycosylation. Second, morpholino knockdown of the zebrafish b3gnt1 orthologue caused characteristic muscular defects and reduced αDG glycosylation. These functional studies identify an important role of B3GNT1 in the synthesis of the uncharacterized laminin-binding glycan of αDG and implicate B3GNT1 as a novel causative gene for WWS.
- Wellcome Trust United Kingdom
- Wellcome Sanger Institute United Kingdom
- Queen Mary University of London United Kingdom
- Radboud University Nijmegen Netherlands
- University of Toronto Canada
Male, Glycosylation, Muscular Dystrophies, Cohort Studies, Limb-Girdle, 2.1 Biological and endogenous factors, Muscular Dystrophy, anzsrc-for: 31 Biological Sciences, Dystroglycans, Zebrafish, Cancer, Pediatric, Tumor, IGMD 4: Glycostation disorders, NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory, Prostate Cancer, anzsrc-for: 3101 Biochemistry and Cell Biology, Homozygote, Walker-Warburg Syndrome, Chromosome Mapping, Articles, Pedigree, Phenotype, 5.1 Pharmaceuticals, Gene Knockdown Techniques, Congenital Muscular Dystrophy, DCN PAC - Perception action and control IGMD 4: Glycostation disorders, Female, Protein Binding, Urologic Diseases, 570, Intellectual and Developmental Disabilities (IDD), DCN MP - Plasticity and memory, Mutation, Missense, 610, 3101 Biochemistry and Cell Biology, N-Acetylglucosaminyltransferases, Cell Line, Rare Diseases, IGMD 3: Genomic disorders and inherited multi-system disorders, Cell Line, Tumor, Genetics, Animals, Humans, DCN NN - Brain networks and neuronal communication, NCMLS 6: Genetics and epigenetic pathways of disease IGMD 9: Renal disorder, Infant, Brain Disorders, anzsrc-for: 3105 Genetics, Laboratory Medicine - Radboud University Medical Center, anzsrc-for: 11 Medical and Health Sciences, Gene Expression Regulation, Muscular Dystrophies, Limb-Girdle, Mutation, anzsrc-for: 06 Biological Sciences, Congenital Structural Anomalies, Laminin, Missense, 31 Biological Sciences
Male, Glycosylation, Muscular Dystrophies, Cohort Studies, Limb-Girdle, 2.1 Biological and endogenous factors, Muscular Dystrophy, anzsrc-for: 31 Biological Sciences, Dystroglycans, Zebrafish, Cancer, Pediatric, Tumor, IGMD 4: Glycostation disorders, NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory, Prostate Cancer, anzsrc-for: 3101 Biochemistry and Cell Biology, Homozygote, Walker-Warburg Syndrome, Chromosome Mapping, Articles, Pedigree, Phenotype, 5.1 Pharmaceuticals, Gene Knockdown Techniques, Congenital Muscular Dystrophy, DCN PAC - Perception action and control IGMD 4: Glycostation disorders, Female, Protein Binding, Urologic Diseases, 570, Intellectual and Developmental Disabilities (IDD), DCN MP - Plasticity and memory, Mutation, Missense, 610, 3101 Biochemistry and Cell Biology, N-Acetylglucosaminyltransferases, Cell Line, Rare Diseases, IGMD 3: Genomic disorders and inherited multi-system disorders, Cell Line, Tumor, Genetics, Animals, Humans, DCN NN - Brain networks and neuronal communication, NCMLS 6: Genetics and epigenetic pathways of disease IGMD 9: Renal disorder, Infant, Brain Disorders, anzsrc-for: 3105 Genetics, Laboratory Medicine - Radboud University Medical Center, anzsrc-for: 11 Medical and Health Sciences, Gene Expression Regulation, Muscular Dystrophies, Limb-Girdle, Mutation, anzsrc-for: 06 Biological Sciences, Congenital Structural Anomalies, Laminin, Missense, 31 Biological Sciences
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).130 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!