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.
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Acknowledgements
We thank C.C. Chen and all members of the Campbell laboratory for discussions and technical support; J. Lilien for discussions; J. Vajsar for the MEB fibroblasts; M. Oldstone for the DGFc5 construct; and T. Südhof for the neurexin fusion protein cDNA. We also thank C. Lovig and the University of Iowa Hybridoma Facility, and the University of Iowa Gene Transfer Vector Core, which is supported in part by the Carver Foundation and the NIH. Samples used in this study were provided in part by the National Institute of Child Health and Human Development Brain Bank HD83284. This work was supported by the Muscular Dystrophy Association (R.B., S.A.M., K.P.C.) and the NIH (S.A.M.). D.E.M. was supported by a Cardiovascular Interdisciplinary Research Fellowship and a University of Iowa Biosciences Initiative Fellowship. K.P.C. is an investigator of the Howard Hughes Medical Institute.
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Supplementary information
Supplementary Fig. 1
DGC expression in Largemyd skeletal muscle after LARGE gene transfer. (PDF 175 kb)
Supplementary Fig. 2
Improved morphology and function of Largemyd transduced skeletal muscle. (PDF 209 kb)
Supplementary Fig. 3
Forced expression of POMGnT1 does not improve the functional glycosylation of α-DG. (PDF 283 kb)
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Barresi, R., Michele, D., Kanagawa, M. et al. LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med 10, 696–703 (2004). https://doi.org/10.1038/nm1059
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DOI: https://doi.org/10.1038/nm1059
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