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

Daniel E. Michele, Rita Barresi, Motoi Kanagawa, Fumiaki Saito, Ronald D. Cohn, Jakob S. Satz, James Dollar, Ichizo Nishino, Richard I. Kelley, Hannu Somer, Volker Straub, Katherine D. Mathews, Steven A. Moore and Kevin P. Campbell ()
Additional contact information
Daniel E. Michele: University of Iowa
Rita Barresi: University of Iowa
Motoi Kanagawa: University of Iowa
Fumiaki Saito: University of Iowa
Ronald D. Cohn: University of Iowa
Jakob S. Satz: University of Iowa
James Dollar: Albany Medical College
Ichizo Nishino: National Institute of Neuroscience
Richard I. Kelley: Kennedy Krieger Institute, John Hopkins University
Hannu Somer: Helsinki University Hospital
Volker Straub: University of Iowa
Katherine D. Mathews: University of Iowa
Steven A. Moore: University of Iowa
Kevin P. Campbell: University of Iowa

Nature, 2002, vol. 418, issue 6896, 417-421

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature00837

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