Investigating the functions of LARGE: lessons from mutant mice

The Large gene encodes a predicted glycosyltransferase of undefined biological activity. However, one important target of the protein is known, alpha-dystroglycan. This protein is a key component of the dystrophin-associated glycoprotein in skeletal muscle, which links cytoskeletal actin to the extracellular matrix (ECM), stabilizing the muscle sarcolemmal membrane. alpha-Dystroglycan binds to extracellular proteins such as laminin through a heavily glycosylated mucin-like domain. Functional Large protein is required for full glycosylation and ligand-binding activity of dystroglycan. The role of Large in this pathway was identified by positional cloning of the mutation in the myodystrophy mouse, an animal model of muscular dystrophy that also has defects in the central and peripheral nervous system and retinal abnormalities. Mice deficient in Large are models for a group of human disorders that have defective alpha-dystroglycan glycosylation.