Glycomic analyses of mouse models of congenital muscular dystrophy. J Biol Chem 2011 Jun 17;286(24):21180-90
Date
04/05/2011Pubmed ID
21460210Pubmed Central ID
PMC3122180DOI
10.1074/jbc.M110.203281Scopus ID
2-s2.0-79958747454 (requires institutional sign-in at Scopus site) 68 CitationsAbstract
Dystroglycanopathies are a subset of congenital muscular dystrophies wherein α-dystroglycan (α-DG) is hypoglycosylated. α-DG is an extensively O-glycosylated extracellular matrix-binding protein and a key component of the dystrophin-glycoprotein complex. Previous studies have shown α-DG to be post-translationally modified by both O-GalNAc- and O-mannose-initiated glycan structures. Mutations in defined or putative glycosyltransferase genes involved in O-mannosylation are associated with a loss of ligand-binding activity of α-DG and are causal for various forms of congenital muscular dystrophy. In this study, we sought to perform glycomic analysis on brain O-linked glycan structures released from proteins of three different knock-out mouse models associated with O-mannosylation (POMGnT1, LARGE (Myd), and DAG1(-/-)). Using mass spectrometry approaches, we were able to identify nine O-mannose-initiated and 25 O-GalNAc-initiated glycan structures in wild-type littermate control mouse brains. Through our analysis, we were able to confirm that POMGnT1 is essential for the extension of all observed O-mannose glycan structures with β1,2-linked GlcNAc. Loss of LARGE expression in the Myd mouse had no observable effect on the O-mannose-initiated glycan structures characterized here. Interestingly, we also determined that similar amounts of O-mannose-initiated glycan structures are present on brain proteins from α-DG-lacking mice (DAG1) compared with wild-type mice, indicating that there must be additional proteins that are O-mannosylated in the mammalian brain. Our findings illustrate that classical β1,2-elongation and β1,6-GlcNAc branching of O-mannose glycan structures are dependent upon the POMGnT1 enzyme and that O-mannosylation is not limited solely to α-DG in the brain.
Author List
Stalnaker SH, Aoki K, Lim JM, Porterfield M, Liu M, Satz JS, Buskirk S, Xiong Y, Zhang P, Campbell KP, Hu H, Live D, Tiemeyer M, Wells LAuthor
Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain
Carbohydrates
Disease Models, Animal
Dystroglycans
Galactosyltransferases
Glycomics
Glycosylation
Mannose
Mice
Mice, Knockout
Muscular Dystrophies
Mutation
N-Acetylglucosaminyltransferases
Polysaccharides
