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.

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Persistent URL dx.doi.org/10.1038/ng.2253, hdl.handle.net/1765/54326
Journal Nature Genetics
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/241995 - Genetic and Epigenetic Networks in Cognitive Dysfunction (GENCODYS)
Roscioli, T, Kamsteeg, E.J, Buysse, K, Maystadt, I, van Reeuwijk, J, van den Elzen, C, … van Bokhoven, H. (2012). Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan. Nature Genetics, 44(5), 581–585. doi:10.1038/ng.2253