Journal article
Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
Human molecular genetics, Vol.18(4), pp.621-631
02/15/2009
DOI: 10.1093/hmg/ddn387
PMCID: PMC2638827
PMID: 19017726
Abstract
Hypoglycosylation and reduced laminin-binding activity of α-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 α-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact α-dystroglycan, and solid-phase assays determined laminin binding levels to be ∼50% of normal. In contrast, intact α-dystroglycan is undetectable in the dystrophic Largemyd mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact α-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 α-dystroglycan. In addition, transfer of LARGE produced laminin-binding forms of α-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 α-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.
Details
- Title: Subtitle
- Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
- Creators
- Motoi Kanagawa - 1 Division of Clinical Genetics, Department of Medical GeneticsAkemi Nishimoto - 1 Division of Clinical Genetics, Department of Medical GeneticsTomohiro Chiyonobu - 1 Division of Clinical Genetics, Department of Medical GeneticsSatoshi Takeda - 3 Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima 771-0192, JapanYuko Miyagoe-Suzuki - 4 Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, JapanFan Wang - 1 Division of Clinical Genetics, Department of Medical GeneticsNobuhiro Fujikake - 1 Division of Clinical Genetics, Department of Medical GeneticsMariko Taniguchi - 1 Division of Clinical Genetics, Department of Medical GeneticsZhongpeng Lu - 1 Division of Clinical Genetics, Department of Medical GeneticsMasaji Tachikawa - 1 Division of Clinical Genetics, Department of Medical GeneticsYoshitaka Nagai - 1 Division of Clinical Genetics, Department of Medical GeneticsFumi Tashiro - 2 Division of Stem Cell Regulation Research, Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanJun-Ichi Miyazaki - 2 Division of Stem Cell Regulation Research, Department of Molecular Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanYouichi Tajima - 5 Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, JapanShin'ichi Takeda - 4 Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, JapanTamao Endo - 6 Glycobiology Research Group, Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, JapanKazuhiro Kobayashi - 1 Division of Clinical Genetics, Department of Medical GeneticsKevin P Campbell - 7 Howard Hughes Medical InstituteTatsushi Toda - 1 Division of Clinical Genetics, Department of Medical Genetics
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.18(4), pp.621-631
- Publisher
- Oxford University Press
- DOI
- 10.1093/hmg/ddn387
- PMID
- 19017726
- PMCID
- PMC2638827
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 02/15/2009
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020745602771
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