Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan.
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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.
AuthorsRoscioli, T; Kamsteeg, EJ; Buysse, K; Maystadt, I; van Reeuwijk, J; van den Elzen, C; van Beusekom, E; Riemersma, M; Pfundt, R; Vissers, LE; Schraders, M; Altunoglu, U; Buckley, MF; Brunner, HG; Grisart, B; Zhou, H; Veltman, JA; Gilissen, C; Mancini, GM; Delrée, P; Willemsen, MA; Ramadža, DP; Chitayat, D; Bennett, C; Sheridan, E; Peeters, EA; Tan-Sindhunata, GM; de Die-Smulders, CE; Devriendt, K; Kayserili, H; El-Hashash, OA; Stemple, DL; Lefeber, DJ; Lin, YY; van Bokhoven, H
- Genomic Medicine