Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. Human Molecular Genetics

Karen Buysse, Moniek Riemersma, Gareth Powell, Jeroen van Reeuwijk, David Chitayat, Tony Roscioli, Erik-Jan Kamsteeg, Christa van den Elzen, Ellen van Beusekom, Susan Blaser, Riyana Babul-Hirji, William Halliday, Gavin J Wright, Derek L Stemple, Yung-Yao Lin, Dirk J Lefeber, Hans van Bokhoven

Research output: Contribution to journalArticlepeer-review

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 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.
Original languageEnglish
Pages (from-to)1746-1754
Number of pages9
JournalHum Mol Genet
Volume22
Issue number9
DOIs
Publication statusPublished - 2013

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