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- Title
Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of ?-dystroglycan.
- Authors
Roscioli, Tony; Kamsteeg, Erik-Jan; Buysse, Karen; Maystadt, Isabelle; van Reeuwijk, Jeroen; van den Elzen, Christa; van Beusekom, Ellen; Riemersma, Moniek; Pfundt, Rolph; Vissers, Lisenka E L M; Schraders, Margit; Altunoglu, Umut; Buckley, Michael F; Brunner, Han G; Grisart, Bernard; Zhou, Huiqing; Veltman, Joris A; Gilissen, Christian; Mancini, Grazia M S; Delrée, Paul
- 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 ?-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 ?-dystroglycan. These results implicate ISPD in ?-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.
- Subjects
MULTIPLE organ failure; EYE abnormalities; BRAIN abnormalities; MUSCULAR dystrophy; GLYCOSYLATION; DYSTROGLYCAN; GLYCOSYLTRANSFERASES; HYDROCEPHALUS
- Publication
Nature Genetics, 2012, Vol 44, Issue 5, p581
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2253