LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies.
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.
Barresi
Rita
R
Howard Hughes Medical Institute, Department of Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Michele
Daniel E
DE
Kanagawa
Motoi
M
Harper
Hollie A
HA
Dovico
Sherri A
SA
Satz
Jakob S
JS
Moore
Steven A
SA
Zhang
Wenli
W
Schachter
Harry
H
Dumanski
Jan P
JP
Cohn
Ronald D
RD
Nishino
Ichizo
I
Campbell
Kevin P
KP
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D049030:Dystroglycans; D015316:Genetic Therapy; D006031:Glycosylation; D016695:Glycosyltransferases / Q000172:deficiency*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics / Q000628:therapy; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*
D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D007797:Laminin; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D049030:Dystroglycans; D016695:Glycosyltransferases; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases