title: Synaptic defects in a Drosophila model of congenital muscular dystrophy.
abstract: The congenital muscular dystrophies present in infancy with muscle weakness and are often associated with mental retardation. Many of these inherited disorders share a common etiology: defective O-glycosylation of alpha-dystroglycan, a component of the dystrophin complex. Protein-O-mannosyl transferase 1 (POMT1) is the first enzyme required for the glycosylation of alpha-dystroglycan, and mutations in the POMT1 gene can lead to both Walker-Warburg syndrome (WWS) and limb girdle muscular dystrophy type 2K (LGMD2K). WWS is associated with severe mental retardation and major structural abnormalities in the brain; however, LGMD2K patients display a more mild retardation with no obvious structural defects in the brain. In a screen for synaptic mutants in Drosophila, we identified mutations in the Drosophila ortholog of POMT1, dPOMT1. Because synaptic defects are a plausible cause of mental retardation, we investigated the molecular and physiological defects associated with loss of dPOMT1 in Drosophila. In dPOMT1 mutants, there is a decrease in the efficacy of synaptic transmission and a change in the subunit composition of the postsynaptic glutamate receptors at the neuromuscular junction. We demonstrate that dPOMT1 is required to glycosylate the Drosophila dystroglycan ortholog Dg in vivo, and that this is the likely cause of these synaptic defects because (1) mutations in Dg lead to similar synaptic defects and (2) genetic interaction studies suggest that dPOMT1 and Dg function in the same pathway. These results are consistent with the model that dPOMT1-dependent glycosylation of Dg is necessary for proper synaptic function and raise the possibility that similar synaptic defects occur in the congenital muscular dystrophies.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA.
authors.forename: Yogesh P
authors.initials: YP
authors.lastname: Wairkar
authors.forename: Lee G
authors.initials: LG
authors.lastname: Fradkin
authors.forename: Jasprina N
authors.initials: JN
authors.lastname: Noordermeer
authors.forename: Aaron
authors.initials: A
authors.lastname: DiAntonio
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D049030:Dystroglycans / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006031:Glycosylation; D008364:Mannosyltransferases / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009469:Neuromuscular Junction / Q000503:physiopathology*; D017470:Receptors, Glutamate / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D017470:Receptors, Glutamate; D049030:Dystroglycans; D013779:Tetrodotoxin; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase