Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies

Nature Medicine volume 10, pages 696–703 (2004)Cite this article

Abstract

Several congenital muscular dystrophies caused by defects in known or putative glycosyltransferases are commonly associated with hypoglycosylation of α-dystroglycan (α-DG) and a marked reduction of its receptor function. We have investigated changes in the processing and function of α-DG resulting from genetic manipulation of LARGE, the putative glycosyltransferase mutated both in Largemyd mice and in humans with congenital muscular dystrophy 1D (MDC1D). Here we show that overexpression of LARGE ameliorates the dystrophic phenotype of Largemyd mice and induces the synthesis of glycan-enriched α-DG with high affinity for extracellular ligands. Notably, LARGE circumvents the α-DG glycosylation defect in cells from individuals with genetically distinct types of congenital muscular dystrophy. Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores α-DG receptor function, whereby glycan-enriched α-DG coordinates the organization of laminin on the cell surface. Our findings indicate that modulation of LARGE expression or activity is a viable therapeutic strategy for glycosyltransferase-deficient congenital muscular dystrophies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expression of LARGE generates heavily glycosylated α-DG.
Figure 2: LARGE generates functional α-DG in FCMD myoblasts.
Figure 3: Rescue of functional α-DG in MEB fibroblasts.
Figure 4: LARGE induces the synthesis of functional α-DG in WWS myoblasts and myotubes.
Figure 5: Laminin clustering correlates with high α-DG–laminin affinity.
Figure 6: Effect of LARGE on α-DG glycosylation.

Similar content being viewed by others

References

  1. Dubowitz, V. Congenital muscular dystrophy: an expanding clinical syndrome. Ann. Neurol. 47, 143–144 (2000).

    Article  Google Scholar 

  2. Toda, T., Kobayashi, K., Kondo-Iida, E., Sasaki, J. & Nakamura, Y. The Fukuyama congenital muscular dystrophy story. Neuromuscul. Disord. 10, 153–159 (2000).

    Article  Google Scholar 

  3. Dobyns, W.B. et al. Diagnostic criteria for Walker-Warburg syndrome. Am. J. Med. Genet. 32, 195–210 (1989).

    Article  Google Scholar 

  4. Yoshida, A. et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell 1, 717–724 (2001).

    Article  Google Scholar 

  5. Beltran-Valero De Bernabe, D. et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am. J. Hum. Genet. 71, 1033–1043 (2002).

    Article  Google Scholar 

  6. Taniguchi, K. et al. Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum. Mol. Genet. 12, 527–534 (2003).

    Article  Google Scholar 

  7. Hayashi, Y.K. et al. Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57, 115–121 (2001).

    Article  Google Scholar 

  8. Kano, H. et al. Deficiency of α-dystroglycan in muscle-eye-brain disease. Biochem. Biophys. Res. Commun. 291, 1283–1286 (2002).

    Article  Google Scholar 

  9. Jimenez-Mallebrera, C. et al. Profound skeletal muscle depletion of α-dystroglycan in Walker-Warburg syndrome. Eur. J. Paediatr. Neurol. 7, 129–137 (2003).

    Article  Google Scholar 

  10. Ervasti, J.M. & Campbell, K.P. Membrane organization of the dystrophin-glycoprotein complex. Cell 66, 1121–1131 (1991).

    Article  Google Scholar 

  11. Holt, K.H., Crosbie, R.H., Venzke, D.P. & Campbell, K.P. Biosynthesis of dystroglycan: processing of a precursor propeptide. FEBS Lett. 468, 79–83 (2000).

    Article  Google Scholar 

  12. Ibraghimov-Beskrovnaya, O. et al. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355, 696–702 (1992).

    Article  Google Scholar 

  13. Michele, D.E. et al. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418, 417–422 (2002).

    Article  Google Scholar 

  14. Takeda, S. et al. Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum. Mol. Genet. 12, 1449–1459 (2003).

    Article  Google Scholar 

  15. Holzfeind, P.J. et al. Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Largemyd mouse defines a natural model for glycosylation-deficient muscle-eye-brain disorders. Hum. Mol. Genet. 11, 2673–2687 (2002).

    Article  Google Scholar 

  16. Grewal, P.K., Holzfeind, P.J., Bittner, R.E. & Hewitt, J.E. Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse. Nat. Genet. 28, 151–154 (2001).

    Article  Google Scholar 

  17. Longman, C. et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of α-dystroglycan. Hum. Mol. Genet. 12, 2853–2861 (2003).

    Article  Google Scholar 

  18. Peyrard, M. et al. The human LARGE gene from 22q12.3–q13.1 is a new, distinct member of the glycosyltransferase gene family. Proc. Natl. Acad. Sci. USA 96, 598–603 (1999).

    Article  Google Scholar 

  19. Kondo-Iida, E. et al. Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum. Mol. Genet. 8, 2303–2309 (1999).

    Article  Google Scholar 

  20. Cohn, R.D. et al. Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration. Cell 110, 639–648 (2002).

    Article  Google Scholar 

  21. Saito, Y., Mizuguchi, M., Oka, A. & Takashima, S. Fukutin protein is expressed in neurons of the normal developing human brain but is reduced in Fukuyama-type congenital muscular dystrophy brain. Ann. Neurol. 47, 756–764 (2000).

    Article  Google Scholar 

  22. Zhang, W., Betel, D. & Schachter, H. Cloning and expression of a novel UDP-GlcNAc:α-D-mannoside β1,2-N-acetylglucosaminyltransferase homologous to UDP-GlcNAc:α-3-D-mannoside β1,2-N-acetylglucosaminyltransferase I. Biochem. J. 361, 153–162 (2002).

    Article  Google Scholar 

  23. Ervasti, J.M. & Campbell, K.P. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J. Cell Biol. 122, 809–823 (1993).

    Article  Google Scholar 

  24. Chiba, A. et al. Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve α-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of α-dystroglycan with laminin. J. Biol. Chem. 272, 2156–2162 (1997).

    Article  Google Scholar 

  25. Zhang, W. et al. Enzymatic diagnostic test for muscle-eye-brain type congenital muscular dystrophy using commercially available reagents. Clin. Biochem. 36, 339–344 (2003).

    Article  Google Scholar 

  26. Jurado, L.A., Coloma, A. & Cruces, J. Identification of a human homolog of the Drosophila rotated abdomen gene (POMT1) encoding a putative protein O-mannosyl-transferase, and assignment to human chromosome 9q34.1. Genomics 58, 171–180 (1999).

    Article  Google Scholar 

  27. Sabatelli, P. et al. Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker-Warburg syndrome caused by POMT1 mutation. Biochim. Biophys. Acta 1638, 57–62 (2003).

    Article  Google Scholar 

  28. Ishii, H., Hayashi, Y.K., Nonaka, I. & Arahata, K. Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy. Neuromuscul. Disord. 7, 191–197 (1997).

    Article  Google Scholar 

  29. Cohen, M.W., Jacobson, C., Yurchenco, P.D., Morris, G.E. & Carbonetto, S. Laminin-induced clustering of dystroglycan on embryonic muscle cells: comparison with agrin-induced clustering. J. Cell Biol. 136, 1047–1058 (1997).

    Article  Google Scholar 

  30. Henry, M.D. & Campbell, K.P. A role for dystroglycan in basement membrane assembly. Cell 95, 859–870 (1998).

    Article  Google Scholar 

  31. Xia, B. et al. Overexpression of the CT GalNAc transferase in skeletal muscle alters myofiber growth, neuromuscular structure, and laminin expression. Dev. Biol. 242, 58–73 (2002).

    Article  Google Scholar 

  32. Nguyen, H.H., Jayasinha, V., Xia, B., Hoyte, K. & Martin, P.T. Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice. Proc. Natl. Acad. Sci. USA 99, 5616–5621 (2002).

    Article  Google Scholar 

  33. Longman, C. et al. Novel forms of muscular dystrophy with α-dystroglycan deficiency and absent CNS involvement. Neuromuscul. Disord. 13, 645 (2003).

    Google Scholar 

  34. Kunz, S., Sevilla, N., McGavern, D.B., Campbell, K.P. & Oldstone, M.B. Molecular analysis of the interaction of LCMV with its cellular receptor α-dystroglycan. J. Cell Biol. 155, 301–310 (2001).

    Article  Google Scholar 

  35. Duclos, F. et al. Progressive muscular dystrophy in α-sarcoglycan-deficient mice. J. Cell Biol. 142, 1461–1471 (1998).

    Article  Google Scholar 

  36. Durbeej, M. et al. Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy. Proc. Natl. Acad. Sci. USA 100, 8910–8915 (2003).

    Article  Google Scholar 

  37. Kobayashi, K. et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394, 388–392 (1998).

    Article  Google Scholar 

  38. Kanoff, R.J. et al. Walker-Warburg syndrome: neurologic features and muscle membrane structure. Pediatr. Neurol. 18, 76–80 (1998).

    Article  Google Scholar 

  39. Henry, M.D. et al. Distinct roles for dystroglycan, β1 integrin and perlecan in cell surface laminin organization. J. Cell Sci. 114, 1137–1144 (2001).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank C.C. Chen and all members of the Campbell laboratory for discussions and technical support; J. Lilien for discussions; J. Vajsar for the MEB fibroblasts; M. Oldstone for the DGFc5 construct; and T. Südhof for the neurexin fusion protein cDNA. We also thank C. Lovig and the University of Iowa Hybridoma Facility, and the University of Iowa Gene Transfer Vector Core, which is supported in part by the Carver Foundation and the NIH. Samples used in this study were provided in part by the National Institute of Child Health and Human Development Brain Bank HD83284. This work was supported by the Muscular Dystrophy Association (R.B., S.A.M., K.P.C.) and the NIH (S.A.M.). D.E.M. was supported by a Cardiovascular Interdisciplinary Research Fellowship and a University of Iowa Biosciences Initiative Fellowship. K.P.C. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Department of Neurology, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Rita Barresi, Daniel E Michele, Motoi Kanagawa, Hollie A Harper, Sherri A Dovico, Jakob S Satz, Ronald D Cohn & Kevin P Campbell

  2. Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Steven A Moore

  3. Department of Biochemistry, Hospital for Sick Children, University of Toronto, Ontario, M5G 1X8, Canada

    Wenli Zhang & Harry Schachter

  4. Department of Genetics and Pathology, Uppsala University, Uppsala, 75185, Sweden

    Jan P Dumanski

  5. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan

    Ichizo Nishino

Authors
  1. Rita Barresi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel E Michele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Motoi Kanagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hollie A Harper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sherri A Dovico
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jakob S Satz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven A Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wenli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Harry Schachter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jan P Dumanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ronald D Cohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ichizo Nishino
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kevin P Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin P Campbell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

DGC expression in Largemyd skeletal muscle after LARGE gene transfer. (PDF 175 kb)

Supplementary Fig. 2

Improved morphology and function of Largemyd transduced skeletal muscle. (PDF 209 kb)

Supplementary Fig. 3

Forced expression of POMGnT1 does not improve the functional glycosylation of α-DG. (PDF 283 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barresi, R., Michele, D., Kanagawa, M. et al. LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med 10, 696–703 (2004). https://doi.org/10.1038/nm1059

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1059

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing