title: [Pathomechanism and therapeutic strategy of Fukuyama congenital muscular dystrophy and related disorders].
abstract: Hypoglycosylation and reduced laminin-binding activity of alpha-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. We previously identified the genes for Fukuyama congenital muscular dystrophy (FCMD) and muscle-eye-brain disease (MEB). FCMD, caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. Knock-in mice carrying the founder retrotransposal insertion exhibited hypoglycosylated alpha-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact alpha-dystroglycan, and solid-phase assays determined laminin binding levels to be approximately 50% of normal. In contrast, intact alpha-dystroglycan is undetectable in the dystrophic Large mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact alpha-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. Transfer of fukutin into knock-in mice restored glycosylation of alpha-dystroglycan. Transfer of LARGE produced laminin-binding forms of alpha-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse. These data suggest that even partial restoration of alpha-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.
authors.affiliation: Division of Neurology, Kobe University Graduate School of Medicine.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000818:Animals; D049030:Dystroglycans; D006031:Glycosylation; D006801:Humans; D007797:Laminin; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009136:Muscular Dystrophies / Q000151:congenital / Q000209:etiology* / Q000628:therapy*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000502:physiology
chemical_list: C113587:FKTN protein, human; D007797:Laminin; D008565:Membrane Proteins; D049030:Dystroglycans; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase