Journal article
Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies
Nature (London), Vol.418(6896), pp.417-422
2002
DOI: 10.1038/nature00837
PMID: 12140558
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.
Details
- Title: Subtitle
- Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies
- Creators
- Daniel E MICHELE - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesRita BARRESL - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesVolker STRAUB - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesKatherine D MATHEWS - Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242-1101, United StatesSteven A MOORE - Department of Pathology, University of Iowa, Iowa City, Iowa 52242-1101, United StatesKevin P CAMPBELL - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesMotol KANAGAWA - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesFumiaki Saito - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesRonald COHN - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesJakeb S SATZ - Howard Hughs Medical Institute, Department of Physiology and Biophysics, and Department of Neurology University of Iowa, Iowa City, Iowa 52242-1101, United StatesJames DOLLAR - Department of Pathology, Albany Medical College, Albany, New York 12208, United StatesIchizo NISHINO - Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo 187-8502, JapanRichard I KELLEY - Kennedy Krieger Institute, John Hopkins University, Baltimore, Maryland 21205, United StatesMannu SOMER - Department of Neurology, Helsinki University Hospital, 00029 HUS Helsinki, Finland
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.418(6896), pp.417-422
- Publisher
- Nature Publishing; London
- DOI
- 10.1038/nature00837
- PMID
- 12140558
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 2002
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984013921002771
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