LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies

Rita Barresi, Daniel E. Michele, Motoi Kanagawa, Hollie A. Harper, Sherri A. Dovico, Jakob S. Satz, Steven A. Moore, Wenli Zhang, Harry Schachter, Jan P. Dumanski, Ronald D. Cohn, Ichizo Nishino, Kevin P. Campbell

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)696-703
Number of pages8
JournalNature medicine
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Barresi, R., Michele, D. E., Kanagawa, M., Harper, H. A., Dovico, S. A., Satz, J. S., Moore, S. A., Zhang, W., Schachter, H., Dumanski, J. P., Cohn, R. D., Nishino, I., & Campbell, K. P. (2004). LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nature medicine, 10(7), 696-703. https://doi.org/10.1038/nm1059