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.
Highlights
Dystroglycanopathy is a major class of congenital muscular dystrophy that is caused by a deficiency of functional glycans on a-dystroglycan (a-DG) with laminin-binding activity
The functionally relevant glycan structure of a-DG has not been well delineated, notwithstanding that several mutants associated with dystroglycanopathy have been identified in fukutin[14], fukutin-related protein (FKRP)[15], UDP-GlcNAc:bGal b-1,3-N-acetylglucosaminyltransferase 1 www.nature.com/scientificreports (B3GNT1)[16], isoprenoid synthase domain containing (ISPD)[17,18,19], and transmembrane protein 5 (TMEM5)[19], which are associated with impaired formation of a-DG laminin-binding glycans
AGO61-KO mice lacked laminin-binding glycans and exhibited phenotypes similar to those of known dystroglycanopathy mutants, as reflected by abnormalities in neural migration and basal lamina formation (Figs. 1 and 2). These defects were observed in dystroglycanopathy mouse models with mutations of DG, fukutin, B3GNT1, or ISPD, due to a lack of laminin-binding glycans displayed on a-DG24–26
Summary
Dystroglycanopathy is a major class of congenital muscular dystrophy that is caused by a deficiency of functional glycans on a-dystroglycan (a-DG) with laminin-binding activity. Dystroglycanopathy is a group of these diseases associated with brain and eye abnormalities at the severe end of the clinical spectrum, including Walker–Warburg syndrome (WWS), muscle-eye-brain (MEB) diseases, Fukuyama-type congenital muscular dystrophy (FCMD), and congenital muscular dystrophy type 1D (MDC1D) The hallmark of these diseases is hypoglycosylation of a-dystroglycan (a-DG)[1,2], which along with b-DG is cleaved from a precursor protein encoded for by a single gene by post-translational processing[3]. AGO61 ( known as GTDC2) was newly identified as a causative gene product associated with WWS based on the results of whole-exome sequencing, homozygosity mapping, and morpholino-mediated knockdown of an AGO61 zebrafish ortholog[20] It was subsequently characterized as a protein O-mannose b-1,4-N-acetylglucosaminyltransferase (POMGnT2) based on its in vitro enzymatic activities against a synthetic peptide substrate carrying a single OMan[21]. We characterized the phenotypes of AGO61-knockout mice and determined that AGO61 mediated the formation of laminin-binding glycans on a-DG
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