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

2012; Nature Portfolio; Volume: 44; Issue: 5 Linguagem: Inglês

10.1038/ng.2253

1546-1718

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 Altunoğlu, Michael F. Buckley, Han G. Brunner, Bernard Grisart, Huiqing Zhou, Joris A. Veltman, Christian Gilissen, Grazia M.S. Mancini, P. Delrée, Michèl A.A.P. Willemsen, Danijela Petković Ramadža, David Chitayat, Christopher Bennett, Eamonn Sheridan, E Peeters, Gita Tan-Sindhunata, C 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,

Physiological and biochemical adaptations

Hans van Bokhoven and colleagues report mutations in the ISPD gene as a cause of Walker-Warburg syndrome. Knockdown of ispd in zebrafish causes hydrocephalus, reduced eye size, muscle degeneration and α-dystroglycan hypoglycosylation. Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant α-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 α-dystroglycan. These results implicate ISPD in α-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.