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

Nature volume 418, pages 417–421 (2002)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Department of Physiology and Biophysics, and Department of Neurology, University of Iowa, Iowa, 52242-1101, Iowa City, USA

    Daniel E. Michele, Rita Barresi, Motoi Kanagawa, Fumiaki Saito, Ronald D. Cohn, Jakob S. Satz, Volker Straub & Kevin P. Campbell

  2. Department of Pediatrics, University of Iowa, Iowa City, Iowa, 52242-1101, USA

    Katherine D. Mathews

  3. Department of Pathology, University of Iowa, Iowa City, Iowa, 52242-1101, USA

    Steven A. Moore

  4. Department of Pathology, Albany Medical College, Albany, New York, 12208, USA

    James Dollar

  5. Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo, 187-8502, Japan

    Ichizo Nishino

  6. Kennedy Krieger Institute, John Hopkins University, Baltimore, Maryland, 21205, USA

    Richard I. Kelley

  7. Department of Neurology, Helsinki University Hospital, Helsinki, 00029 HUS, Finland

    Hannu Somer

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  1. Daniel E. Michele
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Correspondence to Kevin P. Campbell.

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Michele, D., Barresi, R., Kanagawa, M. et al. Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophies. Nature 418, 417–421 (2002). https://doi.org/10.1038/nature00837

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