1. Howard Hughes Medical Institute, Department of Physiology and Biophysics, and Department of Neurology, University of Iowa, Iowa City, Iowa 52242-1101, USA
2. Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242-1101, USA
3. Department of Pathology, University of Iowa, Iowa City, Iowa 52242-1101, USA
4. Department of Pathology, Albany Medical College, Albany, New York 12208, USA
5. Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo 187-8502, Japan
6. Kennedy Krieger Institute, John Hopkins University, Baltimore, Maryland 21205, USA
7. Department of Neurology, Helsinki University Hospital, 00029 HUS Helsinki, Finland

Correspondence to: Kevin P. Campbell¹ Correspondence and requests for materials should be addressed to K.P.C. (e-mail: Email: kevin-campbell@uiowa.edu).

Abstract

Muscle–eye–brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations^{1, 2}. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase^{3, 4}. Here we show, in both MEB and FCMD patients, that -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 -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.

1. Howard Hughes Medical Institute, Department of Physiology and Biophysics, and Department of Neurology, University of Iowa, Iowa City, Iowa 52242-1101, USA
2. Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242-1101, USA
3. Department of Pathology, University of Iowa, Iowa City, Iowa 52242-1101, USA
4. Department of Pathology, Albany Medical College, Albany, New York 12208, USA
5. Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo 187-8502, Japan
6. Kennedy Krieger Institute, John Hopkins University, Baltimore, Maryland 21205, USA
7. Department of Neurology, Helsinki University Hospital, 00029 HUS Helsinki, Finland

Correspondence to: Kevin P. Campbell¹ Correspondence and requests for materials should be addressed to K.P.C. (e-mail: Email: kevin-campbell@uiowa.edu).