Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
| Autor: | Akemi Nishimoto, Zhongpeng Lu, Kazuhiro Kobayashi, Youichi Tajima, Fan Wang, Motoi Kanagawa, Fumi Tashiro, Shin'ichi Takeda, Nobuhiro Fujikake, Kevin P. Campbell, Tatsushi Toda, Yuko Miyagoe-Suzuki, Mariko Taniguchi, Yoshitaka Nagai, Tomohiro Chiyonobu, Tamao Endo, Jun-ichi Miyazaki, Masaji Tachikawa, Satoshi Takeda |
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| Rok vydání: | 2008 |
| Předmět: |
musculoskeletal diseases
Glycosylation animal structures N-Acetylglucosaminyltransferases Muscular Dystrophies Mice chemistry.chemical_compound Transferases Laminin Genetics medicine Dystroglycan Animals Humans Gene Knock-In Techniques Muscular dystrophy Dystroglycans Muscle Skeletal Laminin binding Molecular Biology Genetics (clinical) biology Proteins Articles General Medicine medicine.disease Fukutin Molecular biology Mice Inbred C57BL Disease Models Animal Mutagenesis Insertional chemistry biology.protein Congenital muscular dystrophy Dystrophin Protein Binding |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. Fukuyama-type congenital muscular dystrophy (FCMD), caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. A retrotransposal insertion in fukutin is seen in almost all cases of FCMD. To better understand the molecular pathogenesis of dystroglycanopathies and to explore therapeutic strategies, we generated knock-in mice carrying the retrotransposal insertion in the mouse fukutin ortholog. Knock-in mice 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(myd) 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. To examine whether glycosylation defects can be restored in vivo, we performed mouse gene transfer experiments. Transfer of fukutin into knock-in mice restored glycosylation of alpha-dystroglycan. In addition, transfer of LARGE produced laminin-binding forms of alpha-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse, which is another model of dystroglycanopathy. Overall, 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. |
| Databáze: | OpenAIRE |
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