title: AGO61-dependent GlcNAc modification primes the formation of functional glycans on α-dystroglycan.
abstract: Dystroglycanopathy is a major class of congenital muscular dystrophy that is caused by a deficiency of functional glycans on α-dystroglycan (α-DG) with laminin-binding activity. A product of a recently identified causative gene for dystroglycanopathy, AGO61, acted in vitro as a protein O-mannose β-1, 4-N-acetylglucosaminyltransferase, although it was not functionally characterized. Here we show the phenotypes of AGO61-knockout mice and demonstrate that AGO61 is indispensable for the formation of laminin-binding glycans of α-DG. AGO61-knockout mouse brain exhibited abnormal basal lamina formation and a neuronal migration defect due to a lack of laminin-binding glycans. Furthermore, our results indicate that functional α-DG glycosylation was primed by AGO61-dependent GlcNAc modifications of specific threonine-linked mannosyl moieties of α-DG. These findings provide a key missing link for understanding how the physiologically critical glycan motif is displayed on α-DG and provides new insights on the pathological mechanisms of dystroglycanopathy.
authors.affiliation: 1] Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan [2].
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yagi
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakagawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
authors.forename: Sz-Wei
authors.initials: SW
authors.lastname: Wu
authors.forename: Kay-Hooi
authors.initials: KH
authors.lastname: Khoo
authors.forename: Shogo
authors.initials: S
authors.lastname: Oka
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D049030:Dystroglycans / Q000737:chemistry* / Q000378:metabolism; D005944:Glucosamine / Q000737:chemistry / Q000378:metabolism*; D016695:Glycosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000032:analysis; D010766:Phosphorylation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D053719:Tandem Mass Spectrometry
chemical_list: D007797:Laminin; D010455:Peptides; D011134:Polysaccharides; D011994:Recombinant Proteins; D049030:Dystroglycans; D016695:Glycosyltransferases; C000602224:AGO61 protein, mouse; D017351:N-Acetylglucosaminyltransferases; D005944:Glucosamine