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

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 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.

SUBMITTER: Roscioli T 

PROVIDER: S-EPMC3378661 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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

Roscioli Tony T   Kamsteeg Erik-Jan EJ   Buysse Karen K   Maystadt Isabelle I   van Reeuwijk Jeroen J   van den Elzen Christa C   van Beusekom Ellen E   Riemersma Moniek M   Pfundt Rolph R   Vissers Lisenka E L M LE   Schraders Margit M   Altunoglu Umut U   Buckley Michael F MF   Brunner Han G HG   Grisart Bernard B   Zhou Huiqing H   Veltman Joris A JA   Gilissen Christian C   Mancini Grazia M S GM   Delrée Paul P   Willemsen Michèl A MA   Ramadža Danijela Petković DP   Chitayat David D   Bennett Christopher C   Sheridan Eamonn E   Peeters Els A J EA   Tan-Sindhunata Gita M B GM   de Die-Smulders Christine E CE   Devriendt Koenraad K   Kayserili Hülya H   El-Hashash Osama Abd El-Fattah OA   Stemple Derek L DL   Lefeber Dirk J DJ   Lin Yung-Yao YY   van Bokhoven Hans H  

Nature genetics 20120501 5

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 obscur  ...[more]

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