PUBLICATION

Missense mutations in beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome

Authors
Buysse, K., Riemersma, M., Powell, G., van Reeuwijk, J., Chitayat, D., Roscioli, T., Kamsteeg, E.J., van den Elzen, C., van Beusekomm, E., Blaser, S., Babul-Hirji, R., Halliday, W., Wright, G.J., Stemple, D.L., Lin, Y.Y., Lefeber, D.J., and van Bokhoven, H.
ID
ZDB-PUB-130208-6
Date
2013
Source
Human molecular genetics   22(9): 1746-1754 (Journal)
Registered Authors
Lin, Yung-Yao, Powell, Gareth, Stemple, Derek L., Wright, Gavin J.
Keywords
none
MeSH Terms
  • Animals
  • Cell Line, Tumor
  • Chromosome Mapping
  • Cohort Studies
  • Dystroglycans/metabolism
  • Female
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Glycosylation
  • Homozygote
  • Humans
  • Infant
  • Laminin/metabolism
  • Male
  • Muscular Dystrophies, Limb-Girdle/genetics
  • Mutation, Missense*
  • N-Acetylglucosaminyltransferases/genetics*
  • N-Acetylglucosaminyltransferases/metabolism
  • Pedigree
  • Phenotype
  • Protein Binding
  • Walker-Warburg Syndrome/genetics*
  • Walker-Warburg Syndrome/pathology
  • Zebrafish/genetics
PubMed
23359570 Full text @ Hum. Mol. Genet.
Abstract

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 characterised 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 wildtype 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 for B3GNT1 in the synthesis of the uncharacterised laminin-binding glycan of αDG and implicate B3GNT1 as a novel causative gene for WWS.

Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes