2. Academic Validation
  3. Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan

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

Affiliation

  • 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.

Figures