[Recent Advances in α-dystroglycanopathy].

ABSTRACT

Fukuyama-type congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS) are autosomal recessive disorders characterized by congenital muscular dystrophy with structural brain and eye abnormalities. Aberrant glycosylation of α-dystroglycan (α-DG) is a common pathomechanism of these disorders. In addition, genetic and glycobiological evidence has shown that abnormal glycosylation of α-DG is also seen in several forms of congenital and limb-girdle-type muscular dystrophies. These disorders are collectively called "α-dystroglycanopathy" and nowadays, this term is widely accepted because it is useful for illustrating a complicated genotype-phenotype correlation of these disorders. α-DG is a membrane-associated protein that interacts with extracellular matrix proteins such as laminin, and abnormal glycosylation of α-DG results in loss of its laminin-binding activity. A number of serine/threonine residues are present in the mucin-like domain of α-DG and are majorly composed of sugar chains. Among these glycans, an O-mannosyl tetrasaccharide (Neu5Ac-α2,3-Gal-ß1,4-GlcNAc-ß1,2-Man) is important for laminin-binding activity of α-DG. POMT1/2 and POMGnT1, protein products of causative genes of WWS and MEB, respectively, are enzymes that directly catalyze the biosynthesis of this glycan. Recent studies have suggested that a phosphodiester-linked structure on O-mannose is also important for the laminin-binding activity and that mutations in other causative genes of α-dystroglycanopathy, such as fukutin (originally identified as the gene responsible for FCMD) and LARGE, disrupt the post-phosphoryl structure. Here, we review the history of basic and clinical research on α-dystroglycanopathy and refine its clinical spectrum, which should be broadly extended. In addition, we reveal some progress in research on α-dystroglycanopathy including a novel disease mechanism and anti-sense oligonucleotide therapy for FCMD.