Nature Medicine10, 696 - 703 (2004)
Published online: 6 June 2004; | doi:10.1038/nm1059
LARGE can functionally bypass -dystroglycan glycosylation defects in distinct congenital muscular dystrophies
Rita Barresi1, Daniel E Michele1, Motoi Kanagawa1, Hollie A Harper1, Sherri A Dovico1, Jakob S Satz1, Steven A Moore2, Wenli Zhang3, Harry Schachter3, Jan P Dumanski4, Ronald D Cohn1, Ichizo Nishino5
& Kevin P Campbell1
1
Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
2
Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
3
Hospital for Sick Children, Department of Biochemistry, University of Toronto, Ontario M5G 1X8, Canada.
4
Department of Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden.
5
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
Several congenital muscular dystrophies caused by defects in known or putative glycosyltransferases are commonly associated with hypoglycosylation of -dystroglycan (-DG) and a marked reduction of its receptor function. We have investigated changes in the processing and function of -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 -DG with high affinity for extracellular ligands. Notably, LARGE circumvents the -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 -DG receptor function, whereby glycan-enriched -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.
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-dystroglycan glycosylation defects in distinct congenital muscular dystrophies
-dystroglycan (
