Ellen van Beusekom

Publications (2)43.17 Total impact

• Article: Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome.

  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
  [show abstract] [hide abstract]
  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.
  Human Molecular Genetics 01/2013; · 7.64 Impact Factor
• Source

  Available from: Tony Roscioli

  Article: Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan.

  Tony Roscioli, Erik-Jan Kamsteeg, Karen Buysse, Isabelle Maystadt, Jeroen van Reeuwijk, Christa van den Elzen, Ellen van Beusekom, Moniek Riemersma, Rolph Pfundt, Lisenka E L M Vissers, [......], Els A J Peeters, Gita M B Tan-Sindhunata, Christine E de Die-Smulders, Koenraad Devriendt, Hülya Kayserili, Osama Abd El-Fattah El-Hashash, Derek L Stemple, Dirk J Lefeber, Yung-Yao Lin, Hans van Bokhoven
  [show abstract] [hide abstract]
  ABSTRACT: Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.
  Nature Genetics 04/2012; 44(5):581-5. · 35.53 Impact Factor