Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of alpha-dystroglycan
SourceNature Genetics, 44, 5, (2012), pp. 581-5
Article / Letter to editor
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Laboratory of Genetic, Endocrine and Metabolic Diseases
Paediatrics - OUD tm 2017
SubjectDCN MP - Plasticity and memory; DCN NN - Brain networks and neuronal communication; DCN PAC - Perception action and control IGMD 4: Glycostation disorders; IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 4: Glycostation disorders; NCMLS 6: Genetics and epigenetic pathways of disease; NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory; NCMLS 6: Genetics and epigenetic pathways of disease DCN MP: Plasticity and memory; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders
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.
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