Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of alpha-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, Margit Schraders, Umut Altunoglu, Michael F. Buckley, Han G. Brunner, Bernard Grisart, Huiqing Zhou, Joris A. Veltman, Christian Gilissen, Grazia M. S. Mancini, Paul DelreeMichel A. Willemsen, Danijela Petkovic Ramadza, David Chitayat, Christopher Bennett, Eamonn Sheridan, Els A. J. Peeters, Gita M. B. Tan-Sindhunata, Christine E. de Die-Smulders, Koenraad Devriendt, Hulya Kayserili, Osama Abd El-Fattah El-Hashash, Derek L. Stemple, Dirk J. Lefeber, Yung-Yao Lin*, Hans van Bokhoven

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant alpha-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 alpha-dystroglycan. These results implicate ISPD in alpha-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.
Original languageEnglish
Pages (from-to)581–585
JournalNature Genetics
Issue number5
Publication statusPublished - May 2012

Cite this