title: [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-β1,4-GlcNAc-β1,2-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.
authors: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe-city, Hyogo, Japan.
authors: Atsushi
authors: A
authors: Kuga
authors: Motoi
authors: M
authors: Kanagawa
authors: Tatsushi
authors: T
authors: Toda
mesh_terms: D000818:Animals; D049030:Dystroglycans / Q000737:chemistry / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008364:Mannosyltransferases; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011485:Protein Binding; D058494:Walker-Warburg Syndrome / Q000235:genetics*
chemical_list: C483081:DAG1 protein, human; C113587:FKTN protein, human; D007797:Laminin; D008565:Membrane Proteins; D049030:Dystroglycans; C117674:LARGE1 protein, human; D008364:Mannosyltransferases; D017351:N-Acetylglucosaminyltransferases; C082696:protein O-mannosyltransferase