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Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy

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 fo...

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Autores principales: Kanagawa, Motoi, Nishimoto, Akemi, Chiyonobu, Tomohiro, Takeda, Satoshi, Miyagoe-Suzuki, Yuko, Wang, Fan, Fujikake, Nobuhiro, Taniguchi, Mariko, Lu, Zhongpeng, Tachikawa, Masaji, Nagai, Yoshitaka, Tashiro, Fumi, Miyazaki, Jun-Ichi, Tajima, Youichi, Takeda, Shin'ichi, Endo, Tamao, Kobayashi, Kazuhiro, Campbell, Kevin P., Toda, Tatsushi
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638827/
https://www.ncbi.nlm.nih.gov/pubmed/19017726
http://dx.doi.org/10.1093/hmg/ddn387
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author Kanagawa, Motoi
Nishimoto, Akemi
Chiyonobu, Tomohiro
Takeda, Satoshi
Miyagoe-Suzuki, Yuko
Wang, Fan
Fujikake, Nobuhiro
Taniguchi, Mariko
Lu, Zhongpeng
Tachikawa, Masaji
Nagai, Yoshitaka
Tashiro, Fumi
Miyazaki, Jun-Ichi
Tajima, Youichi
Takeda, Shin'ichi
Endo, Tamao
Kobayashi, Kazuhiro
Campbell, Kevin P.
Toda, Tatsushi
author_facet Kanagawa, Motoi
Nishimoto, Akemi
Chiyonobu, Tomohiro
Takeda, Satoshi
Miyagoe-Suzuki, Yuko
Wang, Fan
Fujikake, Nobuhiro
Taniguchi, Mariko
Lu, Zhongpeng
Tachikawa, Masaji
Nagai, Yoshitaka
Tashiro, Fumi
Miyazaki, Jun-Ichi
Tajima, Youichi
Takeda, Shin'ichi
Endo, Tamao
Kobayashi, Kazuhiro
Campbell, Kevin P.
Toda, Tatsushi
author_sort Kanagawa, Motoi
collection PubMed
description 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 Large(myd) 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.
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spelling pubmed-26388272009-02-25 Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy Kanagawa, Motoi Nishimoto, Akemi Chiyonobu, Tomohiro Takeda, Satoshi Miyagoe-Suzuki, Yuko Wang, Fan Fujikake, Nobuhiro Taniguchi, Mariko Lu, Zhongpeng Tachikawa, Masaji Nagai, Yoshitaka Tashiro, Fumi Miyazaki, Jun-Ichi Tajima, Youichi Takeda, Shin'ichi Endo, Tamao Kobayashi, Kazuhiro Campbell, Kevin P. Toda, Tatsushi Hum Mol Genet Articles 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 Large(myd) 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. Oxford University Press 2009-02-15 2008-11-18 /pmc/articles/PMC2638827/ /pubmed/19017726 http://dx.doi.org/10.1093/hmg/ddn387 Text en © 2008 The Author(s)
spellingShingle Articles
Kanagawa, Motoi
Nishimoto, Akemi
Chiyonobu, Tomohiro
Takeda, Satoshi
Miyagoe-Suzuki, Yuko
Wang, Fan
Fujikake, Nobuhiro
Taniguchi, Mariko
Lu, Zhongpeng
Tachikawa, Masaji
Nagai, Yoshitaka
Tashiro, Fumi
Miyazaki, Jun-Ichi
Tajima, Youichi
Takeda, Shin'ichi
Endo, Tamao
Kobayashi, Kazuhiro
Campbell, Kevin P.
Toda, Tatsushi
Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
title Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
title_full Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
title_fullStr Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
title_full_unstemmed Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
title_short Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy
title_sort residual laminin-binding activity and enhanced dystroglycan glycosylation by large in novel model mice to dystroglycanopathy
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638827/
https://www.ncbi.nlm.nih.gov/pubmed/19017726
http://dx.doi.org/10.1093/hmg/ddn387
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