PUBLICATION

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

Authors
Roscioli, T., Kamsteeg, E.J., Buysse, K., Maystadt, I., van Reeuwijk, J., van den Elzen, C., van Beusekom, E., Riemersma, M., Pfundt, R., Vissers, L.E., Schraders, M., Altunoglu, U., Buckley, M.F., Brunner, H.G., Grisart, B., Zhou, H., Veltman, J.A., Gilissen, C., Mancini, G.M., Delrée, P., Willemsen, M.A., Ramadža, D.P., Chitayat, D., Bennett, C., Sheridan, E., Peeters, E.A., Tan-Sindhunata, G.M., de Die-Smulders, C.E., Devriendt, K., Kayserili, H., El-Hashash, O.A., Stemple, D.L., Lefeber, D.J., Lin, Y.Y., and van Bokhoven, H.
ID
ZDB-PUB-120424-27
Date
2012
Source
Nature Genetics   44(5): 581-585 (Journal)
Registered Authors
Lin, Yung-Yao, Stemple, Derek L.
Keywords
none
MeSH Terms
  • Animals
  • Brain/metabolism
  • Brain/pathology
  • Child, Preschool
  • Dystroglycans/metabolism*
  • Embryo, Nonmammalian
  • Eye/metabolism
  • Eye/pathology
  • Glycosylation
  • Humans
  • Mannosyltransferases/genetics
  • Mannosyltransferases/metabolism
  • Muscle Fibers, Skeletal/metabolism
  • Muscle Fibers, Skeletal/pathology
  • Mutation/genetics*
  • Walker-Warburg Syndrome/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics*
PubMed
22522421 Full text @ Nat. Genet.
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 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.

Genes / Markers
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes