Journal
NATURE GENETICS
Volume 44, Issue 5, Pages 581-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2253
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Funding
- Large-Scale Integrating Project GENCODYS-Genetic and Epigenetic Networks in COgnitive DYSfunction [241995]
- European Union
- Australian National Health and Medical Research Council (NHMRC)
- Prinses Beatrix Fund [W.OR09-15]
- Hersenstichting Nederland
- European Molecular Biology Organization (EMBO) [ALTF 805-2009]
- Wellcome Trust [WT 077047/Z/05/Z, WT 077037/Z/05/Z]
- Department of Human Genetics at Nijmegen
- Netherlands Organisation for Health Research and Development (ZonMW) [916-86-016]
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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 alpha-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 alpha-dystroglycan. These results implicate ISPD in alpha-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.
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