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

Motoi Kanagawa, Akemi Nishimoto, Tomohiro Chiyonobu, Satoshi Takeda, Yuko Miyagoe-Suzuki, Fan Wang, Nobuhiro Fujikake, Mariko Taniguchi, Zhongpeng Lu, Masaji Tachikawa, Yoshitaka Nagai, Fumi Tashiro, Jun Ichi Miyazaki, Youichi Tajima, Shin'ichi Takeda, Tamao Endo, Kazuhiro Kobayashi, Kevin P. Campbell, Tatsushi Toda

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)621-631
Number of pages11
JournalHuman molecular genetics
Volume18
Issue number4
DOIs
Publication statusPublished - 03-02-2009

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Dystroglycans
Laminin
Glycosylation
Walker-Warburg Syndrome
Limb-Girdle Muscular Dystrophies
Genes
Muscular Dystrophies
Muscle Cells

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kanagawa, M., Nishimoto, A., Chiyonobu, T., Takeda, S., Miyagoe-Suzuki, Y., Wang, F., ... Toda, T. (2009). Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy. Human molecular genetics, 18(4), 621-631. https://doi.org/10.1093/hmg/ddn387
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. In: Human molecular genetics. 2009 ; Vol. 18, No. 4. pp. 621-631.
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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.",
author = "Motoi Kanagawa and Akemi Nishimoto and Tomohiro Chiyonobu and Satoshi Takeda and Yuko Miyagoe-Suzuki and Fan Wang and Nobuhiro Fujikake and Mariko Taniguchi and Zhongpeng Lu and Masaji Tachikawa and Yoshitaka Nagai and Fumi Tashiro and Miyazaki, {Jun Ichi} and Youichi Tajima and Shin'ichi Takeda and Tamao Endo and Kazuhiro Kobayashi and Campbell, {Kevin P.} and Tatsushi Toda",
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Kanagawa, M, Nishimoto, A, Chiyonobu, T, Takeda, S, Miyagoe-Suzuki, Y, Wang, F, Fujikake, N, Taniguchi, M, Lu, Z, Tachikawa, M, Nagai, Y, Tashiro, F, Miyazaki, JI, Tajima, Y, Takeda, S, Endo, T, Kobayashi, K, Campbell, KP & Toda, T 2009, 'Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy', Human molecular genetics, vol. 18, no. 4, pp. 621-631. https://doi.org/10.1093/hmg/ddn387

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.

In: Human molecular genetics, Vol. 18, No. 4, 03.02.2009, p. 621-631.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy

AU - Kanagawa, Motoi

AU - Nishimoto, Akemi

AU - Chiyonobu, Tomohiro

AU - Takeda, Satoshi

AU - Miyagoe-Suzuki, Yuko

AU - Wang, Fan

AU - Fujikake, Nobuhiro

AU - Taniguchi, Mariko

AU - Lu, Zhongpeng

AU - Tachikawa, Masaji

AU - Nagai, Yoshitaka

AU - Tashiro, Fumi

AU - Miyazaki, Jun Ichi

AU - Tajima, Youichi

AU - Takeda, Shin'ichi

AU - Endo, Tamao

AU - Kobayashi, Kazuhiro

AU - Campbell, Kevin P.

AU - Toda, Tatsushi

PY - 2009/2/3

Y1 - 2009/2/3

N2 - 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.

AB - 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.

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