Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.
Muscle eye brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase. Here we show, in both MEB and FCMD patients, that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin and agrin. We show that this post-translational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice. We demonstrate that myd mice have abnormal neuronal migration in cerebral cortex, cerebellum and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. These results suggest that at least three distinct mammalian genes function within a convergent post-translational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.
Michele
Daniel E
DE
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242-1101, USA.
Barresi
Rita
R
Kanagawa
Motoi
M
Saito
Fumiaki
F
Cohn
Ronald D
RD
Satz
Jakob S
JS
Dollar
James
J
Nishino
Ichizo
I
Kelley
Richard I
RI
Somer
Hannu
H
Straub
Volker
V
Mathews
Katherine D
KD
Moore
Steven A
SA
Campbell
Kevin P
KP
D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D049030:Dystroglycans; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005123:Eye / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006031:Glycosylation; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009132:Muscles / Q000378:metabolism; D009136:Muscular Dystrophies / Q000151:congenital* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational
D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016326:Extracellular Matrix Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D049030:Dystroglycans