Dystroglycan (DG), a heterodimeric transmembrane glycoprotein, is a central component of the dystrophin-glycoprotein complex (DGC) and responsible for a variety of physiological and developmental processes, including muscle stabilization, basement membrane assembly, cell migration and signalling [
1]. The protein is synthesized as a precursor molecule that is post-translationally cleaved into a cell surface α- and a transmembrane β- subunits [
2]. The extracellular subunit, alpha-dystroglycan (αDG), is a highly glycosylated basement membrane protein that acts as a receptor for non-collagenous proteins in the extracellular matrix (ECM) containing laminin globular domains, and for Old World arenaviruses [
1,
3‐
5]. Mutations in the DG-encoding gene
(DAG1) [
6,
7] and several other genes whose products are involved, directly or indirectly, in glycosylation pathway of αDG [
8] have been identified in various forms of congenital and limb-girdle muscular dystrophies (CMD/ LGMDs). These disorders are all associated with hypoglycosylation of αDG and a consequent lack of ligand-binding activity and thus are collectively termed as dystroglycanopathies [
9].
Although the precise glycosylation pathway of αDG is not fully understood, the function of Like-acetylglucosaminyltransferase (LARGE) enzyme has been of particular interest. It is encoded by one of the largest genes (
LARGE) in the human genome [
10‐
12], which is mutated in the myodystrophy mouse (LARGE-myd) [
10,
13] and in patients affected by MDC1D, a subclass of CMD associated with skeletal muscle and structural brain involvement [
11]. The mentioned enzyme is a bifunctional glycosyltransferase, with both xylosyltransferase and glucuronyltransferase activities and plays an important role in the glycosylation pathway of αDG. It transfers a novel heteropolysaccharide structure, repeating units of -glucuronic acid-β1,3-xylose-α1,3- to the basement membrane receptor DG [
14]. This structure has been recently termed as matriglycan, which is bound to the αDG through a phosphorylated
O-mannosyl glycan anchored at Thr317 and Thr319 in the mucin-like domain [
8,
15,
16]. It is required for the αDG to bind laminin-G domain-containing ECM ligands including laminin, agrin, perlecan and neurexin [
4,
17‐
19]. It has been reported that LARGE-dependent matriglycan structure plays an important role for normal skeletal muscle function and the consequent reduction in the amount of glycans on αDG causes structural alterations of the basement membrane, immature neuromuscular junctions and dysfunctional muscle predisposed to dystrophy [
20]. Uniquely, transient overexpression of
LARGE has been shown to increase glycosylation of αDG as evaluated by increased immunoreactivity to antibodies IIH6 and VIA4–1 both of which are known to recognize carbohydrate moieties and leads to a recovery of receptor function in cells derived from patients diagnosed as Fukuyama CMD (FCMD), muscle-eye-brain disease (MEB) and Walker–Warburg syndrome (WWS) [
17]. Also, the identical results has been reported in vivo, after adenovirus or adeno-associated virus mediated gene transfer of
LARGE in
Fukutin (FKTN), Fukutin-related protein (FKRP) and
Protein-O-mannose ß2-N-acetylglucosaminyltransferase 1 (POMGNT1) deficient mice models [
21‐
23]. Although a recent study demonstrates that fukutin is required for the ability of LARGE to hyperglycosylate αDG [
24], this strategy is already regarded as a promising therapeutic approach for preventing/slowing progression of a broad range of dystroglycanopathies regardless of the causative gene defects. However, it remains crucial to analyze such a strategy in different types of muscular dystrophies other than dystroglycanopathy.