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

  • Nat Genet. 2012 May;44(5):581-5. doi: 10.1038/ng.2253.
Tony Roscioli  1 ,  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 ,  Margit Schraders ,  Umut Altunoglu ,  Michael F Buckley ,  Han G Brunner ,  Bernard Grisart ,  Huiqing Zhou ,  Joris A Veltman ,  Christian Gilissen ,  Grazia M S Mancini ,  Paul Delrée ,  Michèl A Willemsen ,  Danijela Petković Ramadža ,  David Chitayat ,  Christopher Bennett ,  Eamonn Sheridan ,  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
Affiliations
  • 1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PMID: 22522421 DOI: 10.1038/ng.2253
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.