Journal article
LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies
Nature medicine, Vol.10(7), pp.696-703
07/2004
DOI: 10.1038/nm1059
PMID: 15184894
Abstract
Several congenital muscular dystrophies caused by defects in known or putative glycosyltransferases are commonly associated with hypoglycosylation of α-dystroglycan (α-DG) and a marked reduction of its receptor function. We have investigated changes in the processing and function of α-DG resulting from genetic manipulation of LARGE, the putative glycosyltransferase mutated both in Largemyd mice and in humans with congenital muscular dystrophy 1D (MDC1D). Here we show that overexpression of LARGE ameliorates the dystrophic phenotype of Largemyd mice and induces the synthesis of glycan-enriched α-DG with high affinity for extracellular ligands. Notably, LARGE circumvents the α-DG glycosylation defect in cells from individuals with genetically distinct types of congenital muscular dystrophy. Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores α-DG receptor function, whereby glycan-enriched α-DG coordinates the organization of laminin on the cell surface. Our findings indicate that modulation of LARGE expression or activity is a viable therapeutic strategy for glycosyltransferase-deficient congenital muscular dystrophies.
Details
- Title: Subtitle
- LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies
- Creators
- Daniel E Michele - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaSherri A Dovico - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaRita Barresi - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaSteven A Moore - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of IowaRonald D Cohn - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaMotoi Kanagawa - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaHollie A Harper - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaWenli Zhang - Hospital for Sick Children, Department of Biochemistry, University of TorontoJan P Dumanski - Department of Genetics and Pathology, Uppsala UniversityKevin P Campbell - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of IowaHarry Schachter - Hospital for Sick Children, Department of Biochemistry, University of TorontoIchizo Nishino - Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, KodairaJakob S Satz - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.10(7), pp.696-703
- DOI
- 10.1038/nm1059
- PMID
- 15184894
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Language
- English
- Date published
- 07/2004
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Internal Medicine
- Record Identifier
- 9984020722302771
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