AGO61-dependent GlcNAc modification primes the formation of functional glycans on ?-dystroglycan.

ABSTRACT: Dystroglycanopathy is a major class of congenital muscular dystrophy that is caused by a deficiency of functional glycans on ?-dystroglycan (?-DG) with laminin-binding activity. A product of a recently identified causative gene for dystroglycanopathy, AGO61, acted in vitro as a protein O-mannose ?-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 ?-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 ?-DG glycosylation was primed by AGO61-dependent GlcNAc modifications of specific threonine-linked mannosyl moieties of ?-DG. These findings provide a key missing link for understanding how the physiologically critical glycan motif is displayed on ?-DG and provides new insights on the pathological mechanisms of dystroglycanopathy.

SUBMITTER: Yagi H 

PROVIDER: S-EPMC3836086 | biostudies-other | 2013

REPOSITORIES: biostudies-other