title: Mutations in ISPD cause Walker-Warburg syndrome and defective  glycosylation of α-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.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Karen
authors.initials: K
authors.lastname: Buysse
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: Christa
authors.initials: C
authors.lastname: van den Elzen
authors.forename: Ellen
authors.initials: E
authors.lastname: van Beusekom
authors.forename: Moniek
authors.initials: M
authors.lastname: Riemersma
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Buckley
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Bernard
authors.initials: B
authors.lastname: Grisart
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.forename: Paul
authors.initials: P
authors.lastname: Delrée
authors.forename: Michèl A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Danijela Petković
authors.initials: DP
authors.lastname: Ramadža
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Christopher
authors.initials: C
authors.lastname: Bennett
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.forename: Els A J
authors.initials: EA
authors.lastname: Peeters
authors.forename: Gita M B
authors.initials: GM
authors.lastname: Tan-Sindhunata
authors.forename: Christine E
authors.initials: CE
authors.lastname: de Die-Smulders
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Osama Abd El-Fattah
authors.initials: OA
authors.lastname: El-Hashash
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Yung-Yao
authors.initials: YY
authors.lastname: Lin
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D049030:Dystroglycans / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D005123:Eye / Q000378:metabolism / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D058494:Walker-Warburg Syndrome / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*
chemical_list: D049030:Dystroglycans; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase