POMK Regulates Dystroglycan Function via LARGE-mediated Elongation of Matriglycan

Protein O-Mannose Kinase (POMK) is a novel muscular dystrophy gene that phosphorylates mannose of core M3 (GalNac-{beta}1,3-GlcNac-{beta}1,4-Man) on -dystroglycan (-DG). Like-acetylglucosaminyltransferase-1 (LARGE) synthesizes matriglycan, a heteropolysaccharide [-GlcA-{beta}1,3-Xyl-{beta}1,3-]n, that enables -DG to function as an extracellular matrix (ECM) receptor. Extension of matriglycan enhances its binding capacity for ECM ligands and is required for skeletal muscle function. However, the mechanisms which regulate LARGE-mediated extension of matriglycan during muscle differentiation are unknown. Here we show that LARGE initiates matriglycan synthesis on -DG without POMK but requires POMK to extend matriglycan to its mature length. Furthermore, mouse and human skeletal muscle lacking POMK express a short, non-extended form of matriglycan and exhibit muscular dystrophy. Our results demonstrate a POMK-dependent mechanism that regulates matriglycan synthesis and -DG receptor function.