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

被引:199
作者
Barresi, R
Michele, DE
Kanagawa, M
Harper, HA
Dovico, SA
Satz, JS
Moore, SA
Zhang, WL
Schachter, H
Dumanski, JP
Cohn, RD
Nishino, I
Campbell, KP [1 ]
机构
[1] Univ Iowa, Coll Med, Howard Hughes Med Inst, Dept Phys & Biophys,Dept Neurol, Iowa City, IA 52242 USA
[2] Univ Iowa, Coll Med, Roy J & Luclle A Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA
[3] Univ Toronto, Hosp Sick Children, Dept Biochem, Toronto, ON M5G 1X8, Canada
[4] Univ Uppsala, Dept Genet & Pathol, S-75185 Uppsala, Sweden
[5] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Neuromuscular Res, Tokyo 1878502, Japan
关键词
D O I
10.1038/nm1059
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several congenital muscular dystrophies caused by defects in known or putative glycosyltransferases are commonly associated with hypoglycosylation of alpha-dystroglycan (alpha-DG) and a marked reduction of its receptor function. We have investigated changes in the processing and function of alpha-DG resulting from genetic manipulation of LARGE, the putative glycosyltransferase mutated both in Large(myd) mice and in humans with congenital muscular dystrophy 1D (MDC1D). Here we show that overexpression of LARGE ameliorates the dystrophic phenotype of Large(myd) mice and induces the synthesis of glycan-enriched alpha-DG with high affinity for extracellular ligands. Notably, LARGE circumvents the alpha-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 alpha-DG receptor function, whereby glycan-enriched alpha-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.
引用
收藏
页码:696 / 703
页数:8
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