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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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.
The authors declare that they have no competing financial interests.
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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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