α-Dystroglycanopathy: Molecular Mechanism, Clinical Manifestations, and Therapeutic Approaches

Abstract

α-Dystroglycanopathy is a general term for diseases that develop due to a gene that encodes a glycosyltransferase that catalyzes the formation of the skeleton of the sugar chain structure of α-dystroglycan (α-DG), and a gene that encodes a protein that is a substrate thereof. It shows an autosomal recessive inheritance pattern, and typical diseases include Fukuyama type congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB) and Walker-Warburg syndrome (WWS). The gene responsible for FCMD is FKTN, whose mutation causes an abnormality in the O-mannose-type sugar chain of α-DG, which is a component of the dystrophin-related glycoprotein complex, due to a loss-of-function mutation of the fukutin protein. As a result, the ability to bind to laminin, a component of the basement membrane, is reduced, thus disrupting the relationship between the basement membrane and the cytoskeleton, which resulted in the development of muscular dystrophy. Patients with FCMD-related diseases such as MEB and WWS were also found to develop congenital muscular dystrophy, and the syndromes including these diseases are referred to as α-dystroglycanopathy. It is known that an insufficient glycosylation of α-DG causes cerebral cortical dysplasia and muscular dystrophy with ocular symptoms, and α-dystroglycanopathies are classified into severe types with cerebral malformations and ocular symptoms in addition to muscular dystrophy. However, in recent years, with the elucidation of the pathological condition, congenital severe muscular dystrophy has been found to be affected by various factors such as the degree of impaired glycosylation of α-DG, changes in the subcellular localization of mutant proteins, and changes in glycosyltransferase activity. It has also been found that there is a wide range of phenotypes from adult-onset limb-girdle muscular dystrophy. At this time, 18 causative genes of α-dystroglycanopathies have been identified, and it is likely that more genes will be reported in the near future. Gene therapy, antisense therapy, and enzyme replacement therapy can lead to the treatment of some types of α-dystroglycanopathies. This paper reports on the molecular mechanism of α-dystroglycanopathies, clinical findings, and therapeutic approaches.