However, recently it has become evident that a number of forms of congenital muscular dystrophy (CMD) and several variants of limb girdle muscular dystrophy (LGMD) are associated with 4-mu cell line mutations in a number of genes encoding for proteins that are either putative or demonstrated glycosyltransferases (1–5). These include four severe forms of CMD that are Inhibitors,research,lifescience,medical associated with severe structural brain involvement and variable associated

eye abnormalities: Walker-Warburg syndrome (WWS), Muscle-Eye-Brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD) and congenital muscular dystrophy type 1D (MDC1D). The CMD variant MDC1C and a relatively mild form of limb girdle muscular dystrophy (LGMD2I) are not typically associated with brain involvement. A characteristic and diagnostic feature of these MD variants is their association with abnormalities in the glycosylation of α-dystroglycan (ADG), and this has led Inhibitors,research,lifescience,medical to the suggestion of the name “dystroglycanopathy” to identify them (6–10). The abnormal glycosylation of ADG was only described in 2001 Inhibitors,research,lifescience,medical but is now a recognized common pathogenetic mechanism responsible for several forms of muscular dystrophy. Mutations in 6 genes have been identified in patients with dystroglycanopathies, initially each associated

with a specific clinical entity. However it is now clear that allelic mutations in each of these 6 genes are Inhibitors,research,lifescience,medical responsible for an extremely wide spectrum of clinical conditions; in addition thorough genetic analysis of these 6 genes in patients

with a dystroglycanopathy only identifies mutations in ~ 65% of cases suggesting that further genetic heterogeneity exists. Glycosylation defects and muscular dystrophies There Inhibitors,research,lifescience,medical are two main forms of protein glycosylation: N-linked glycosylation in which the oligosaccharide is attached to the amide group of an asparagine residue and O-linked glycosylation where the oligosaccharide is attached to a hydroxyl group of a serine or threonine residue. O-mannosylation is a very rare form of glycosylation and in humans only ADG has so far been shown to contain these modified glycans (1, 11–16). ADG is a very heavily glycosylated glycoprotein: while its primary sequence predicts a molecular mass of 72 kDa, its molecular mass in mammalian skeletal and cardiac muscle is Idoxuridine 156 kDa and 140 kDa respectively and in brain and peripheral nerve 120 kDa. Although O-mannosylation does not represent the only form of O-glycosylation on ADG, it is required for binding to a number of LG domain containing extracellular matrix proteins such as laminin, perlecan and agrin in muscle, and neurexin in the brain (17). To date, mutations in 6 known or putative glycosyltranferase genes have been identified in dystroglycanopathies.