Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophies


Muscle–eye–brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations1,2. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase3,4. Here we show, in both MEB and FCMD patients, that α-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin and agrin. We show that this post-translational biochemical and functional disruption of α-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice. We demonstrate that myd mice have abnormal neuronal migration in cerebral cortex, cerebellum and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. These results suggest that at least three distinct mammalian genes function within a convergent post-translational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan–ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Post-translational modification of dystroglycan in MEB and FCMD.
Figure 2: Dystroglycan–ligand interactions in MEB and FCMD.
Figure 3: Post-translational modification of dystroglycan in myd muscle and brain.
Figure 4: Dystroglycan–ligand interactions in myd muscle and brain.
Figure 5: Abnormal neuronal migration and dystroglycan-associated protein targeting in myd mouse brain.


  1. 1

    Dubowitz, V. Congenital muscular dystrophy: an expanding clinical syndrome. Ann. Neurol. 47, 143–144 (2000); erratum Ann. Neurol. 47, 554 (2000)

    CAS  Article  Google Scholar 

  2. 2

    Toda, T. The Fukuyama congenital muscular dystrophy story. Neuromuscul. Disord. 10, 153–159 (2000)

    CAS  Article  Google Scholar 

  3. 3

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

    ADS  CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Henry, M. D. & Campbell, K. P. Dystroglycan inside and out. Curr. Opin. Cell Biol. 11, 602–607 (1999)

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

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

    ADS  CAS  Article  Google Scholar 

  9. 9

    Ibraghimov-Beskrovnaya, O. et al. Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization. Hum. Mol. Genet. 2, 1651–1657 (1993)

    CAS  Article  Google Scholar 

  10. 10

    Hoffman, E. P., Brown, R. H. & Kunkel, L. M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919–928 (1987)

    CAS  Article  Google Scholar 

  11. 11

    Roberds, S. L. et al. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell 78, 625–633 (1994)

    CAS  Article  Google Scholar 

  12. 12

    Lim, L. E. et al. β-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nature Genet. 11, 257–265 (1995)

    CAS  Article  Google Scholar 

  13. 13

    Noguchi, S. et al. Mutations in the dystrophin-associated protein γ-sarcoglycan in chromosome 13 muscular dystrophy. Science 270, 819–822 (1995)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Nigro, V. et al. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the δ-sarcoglycan gene. Nature Genet. 14, 195–198 (1996)

    CAS  Article  Google Scholar 

  15. 15

    Williamson, R. A. et al. Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice. Hum. Mol. Genet. 6, 831–841 (1997)

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

    Gee, S. H., Montanaro, F., Lindenbaum, M. H. & Carbonetto, S. Dystroglycan-α, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell 77, 675–686 (1994)

    CAS  Article  Google Scholar 

  18. 18

    Campanelli, J. T., Roberds, S. L., Campbell, K. P. & Scheller, R. H. A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering. Cell 77, 663–674 (1994)

    CAS  Article  Google Scholar 

  19. 19

    Sugita, S. et al. A stoichiometric complex of neurexins and dystroglycan in brain. J. Cell Biol. 154, 435–445 (2001)

    CAS  Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Haltia, M. Muscle-eye-brain disease: a neuropathological study. Ann. Neurol. 41, 173–180 (1997)

    CAS  Article  Google Scholar 

  22. 22

    Moore, S. A. et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418, 422–425 (2002)

    ADS  CAS  Article  Google Scholar 

  23. 23

    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)

    CAS  Article  Google Scholar 

  24. 24

    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)

    CAS  Article  Google Scholar 

  25. 25

    Barton, L. L. & Mets, M. B. Congenital lymphocytic choriomeningitis virus infection: decade of rediscovery. Clin. Infect. Dis. 33, 370–374 (2001)

    CAS  Article  Google Scholar 

  26. 26

    Jung, D. et al. Characterization of δ-sarcoglycan, a novel component of the oligomeric sarcoglycan complex involved in limb-girdle muscular dystrophy. J. Biol. Chem. 271, 32321–32329 (1996)

    CAS  Article  Google Scholar 

  27. 27

    Engvall, E. et al. Mapping of domains in human laminin using monoclonal antibodies: localization of the neurite-promoting site. J. Cell Biol. 103, 2457–2465 (1986)

    CAS  Article  Google Scholar 

  28. 28

    Matsumura, K. et al. Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy. Nature 359, 320–322 (1992)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Allamand, V. et al. Mild congenital muscular dystrophy in two patients with an internally deleted laminin α2-chain. Hum. Mol. Genet. 6, 747–752 (1997)

    CAS  Article  Google Scholar 

Download references


We thank J. Flanagan, S. Prouty, S. Cutshall and D. Venzke for technical support. We also thank S. Weinstein for obtaining normal human muscle, T. Sudhof for the neurexin fusion protein complementary DNA, S. Froehner for the α-syntrophin antibody, and M. Oldstone for the DGFC5 construct. This work was supported by the Muscular Dystrophy Association and the National Institutes of Health (to 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



Corresponding author

Correspondence to Kevin P. Campbell.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Michele, D., Barresi, R., Kanagawa, M. et al. Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophies. Nature 418, 417–421 (2002).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.