Congenital muscular dystrophies involving the O-mannose pathway

Abstract

A number of forms of congenital muscular dystrophy (CMD) have been identified that involve defects in the glycosylation of dystroglycan with O-mannosyl-linked glycans. There are at least six genes that can affect this type of glycosylation, and defects in these genes give rise to disorders that have many aspects of muscle and brain pathology in common. Overexpression of one gene implicated in CMD, LARGE, was recently shown to increase dystroglycan glycosylation and restore its function in cells taken from CMD patients. Overexpression of Galgt2, a glycosyltransferase not implicated in CMD, also alters dystroglycan glycosylation and inhibits muscular dystrophy in a mouse model of Duchenne muscular dystrophy. These findings suggest that a common approach to therapy in muscular dystrophies may be to increase the glycosylation of dystroglycan with particular glycan structures.

Fig. (1). Dystroglycan glycosylation and its place in the dystrophin-glycoprotein complex

Laminin, which is present in the extracellular matrix surrounding the myofiber membrane, binds to α dystroglycan. This interaction requires the O-mannosyl-linked glycans present in the middle third of the α dystroglycan molecule. α dystroglycan binds to β dystroglycan, which spans the muscle membrane. The intracellular domain of β dystroglycan binds to dystrophin, which links the complex both to actin and to number of signaling components. The sarcoglycans are additional transmembrane components within the dystrophin-associated glycoprotein complex.

Fig. (2). Genes affecting dystroglycan glycosylation associated with congenital muscular dystrophy

The O-mannosyl linked glycans on α dystroglycan are comprised of linear chain of four carbohydrates. There are six genes known to cause congenital muscular dystrophy that alter the glycosylation of dystroglycan on its O-linked chains. POMT1 and POMT2 (defective in Walker Warburg syndrome) are both required to synthesize the O-mannosyl linkage and POMGnT1 (defective in muscle-eye-brain disease) synthesizes the β1,2GlcNAc linkage. Three other genes also likely affect this pathway; fukutin (defective in Fukuyama congenital muscular dystrophy, fukutin-related protein (FKRP, defective in congenital muscular dystrophy 1C, Limb Girdle muscular dystrophy 2I, and WWS), and LARGE (defective in congenital muscular dystrophy 1D). The function of these three genes is not currently known.