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

Nat Genet. 2012 May;44(5):581-5. doi: 10.1038/ng.2253.


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.

Publication types

  • Research Support, Non-U.S. Gov't

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*


  • Dystroglycans
  • Mannosyltransferases
  • protein O-mannosyltransferase