SGK196 Is a Glycosylation-Specific O-Mannose Kinase Required for Dystroglycan Function

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Science  23 Aug 2013:
Vol. 341, Issue 6148, pp. 896-899
DOI: 10.1126/science.1239951

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Dissecting Dystrophies

Defects in α-dystroglycan lead to various congenital muscular dystrophies, and its ability to bind to extracellular matrix (ECM) is dependent on formation of a specific O-linked sugar structure. Previous efforts to understand the molecular mechanisms underlying α-dystroglycan's ability to bind to the ECM led to the identification of a phosphorylated O-mannosyl trisaccharide on α-dystroglycan and to the demonstration that addition of this residue is a prerequisite for formation of the ligand-binding motif. However, the biosynthetic pathway that leads to production of the phosphorylated O-mannosyl glycan has not been delineated. Yoshida-Moriguchi et al. (p. 896, published online 8 August) elucidate the functions of three genes recently found to cause dystroglycan-related disorders and explain the defects in the production of the phosphorylated O-mannosyl glycan that underlie the pathologies of patients with the relevant mutations.


Phosphorylated O-mannosyl trisaccharide [N-acetylgalactosamine–β3-N-acetylglucosamine–β4-(phosphate-6-)mannose] is required for dystroglycan to bind laminin-G domain–containing extracellular proteins with high affinity in muscle and brain. However, the enzymes that produce this structure have not been fully elucidated. We found that glycosyltransferase-like domain–containing 2 (GTDC2) is a protein O-linked mannose β 1,4-N-acetylglucosaminyltransferase whose product could be extended by β 1,3-N-acetylgalactosaminyltransferase2 (B3GALNT2) to form the O-mannosyl trisaccharide. Furthermore, we identified SGK196 as an atypical kinase that phosphorylated the 6-position of O-mannose, specifically after the mannose had been modified by both GTDC2 and B3GALNT2. These findings suggest how mutations in GTDC2, B3GALNT2, and SGK196 disrupt dystroglycan receptor function and lead to congenital muscular dystrophy.

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