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

Daniel E. Michele, Rita Barresi, Motoi Kanagawa, Fumiaki Salto, Ronald D. Cohn, Jakob S. Satz, James Dollar, Ichizo Nishino, Richard I. Kelley, Hannu Somer, Volker Straub, Katherine D. Mathews, Steven A. Moore, Kevin P. Campbell

Research output: Contribution to journalArticlepeer-review

664 Scopus citations


Muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase. 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 posttranslational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.

Original languageEnglish (US)
Pages (from-to)417-422
Number of pages6
Issue number6896
StatePublished - Jul 25 2002

ASJC Scopus subject areas

  • General


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