Defective glycosylation in muscular dystrophy

• Published in: The Lancet (British edition) Vol. 360; no. 9343; pp. 1419 - 1421
• Main Authors: Muntoni, Francesco, Brockington, Martin, Blake, Derek J, Torelli, Silvia, Brown, Susan C
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 02.11.2002; Lancet; Elsevier Limited
• Subjects: Biological and medical sciences; Brain; Brain diseases; Brain research; Cell adhesion & migration; Central nervous system; Congenital diseases; Cytoskeletal Proteins - metabolism; Cytoskeletal Proteins - physiology; Defects; Diseases of striated muscles. Neuromuscular diseases; Dystroglycans; Dystrophy; Enzymes; Epitopes; Extracellular matrix; Eye; Genes; Glycoproteins; Glycosylation; Humans; Insects; Leprosy; Ligands; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Molecular weight; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - physiopathology; Muscular dystrophy; Musculoskeletal system; Mutation; Neurology; Proteins; Signal transduction; Sugar; Human; Proteoglycan; Neuromuscular diseases; Nervous system diseases; Enzyme; Pathogenesis; Transferases; Glycosyltransferases; Glycosylation; Muscular dystrophy; Genetic disease; Defect; Bibliographic review
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(02)11397-3

Over the past 15 years the causative genes of several inherited muscular dystrophies have been identified. These genes encode sarcolemmal, extracellular matrix, sarcomeric, and nuclear envelope proteins. Although the post-translational processing of muscle proteins has a significant role in their correct assembly and function, these processes have not been shown to be primarily involved in the pathogenesis of muscular dystrophies until recently. In the past 18 months, four different forms of inherited muscular dystrophy in human beings have been associated with mutations in genes encoding for putative glycosyltransferases. Aberrant glycosylation of alpha-dystroglycan, an external membrane protein expressed in muscle, brain, and other tissues, is a common feature in these disorders. alpha-dystroglycan is highly glycosylated, its sugar components varying in different tissues and controlling its interaction with extracellular matrix partners. Disrupted glycosylation of alpha-dystroglycan results in a loss of these interactions, giving rise to both progressive muscle degeneration and abnormal neuronal migration in the brain. Kevin Campbell and colleagues have recently demonstrated that patients with muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD), as well as the myodystrophy (myd) mouse, have an abnormally glycosyated form of alpha-dystroglycan (Nature 2002; 418: 417-22 and 422-25). The abnormally glycosylated protein did not bind to three of its extracellular matrix ligands, laminin alpha2 chain, agrin, and neurexin. The investigators also showed that a neuronal migration disorder occurs in both the myd mouse and in a brain-restricted alpha-dystroglycan knock-out mouse that is similar to that seen in patients with MEB and FCMD. These results identify alpha-dystroglycan as having an essential role in both muscle and brain development and function. Emphasis is moving away from identifying the protein components of the muscle fibre that are involved in muscular dystrophies towards the post-translational processing of proteins and the enzymes involved in these modifications. This opens up new avenues of research. Abnormal glycosylation of alpha-dystroglycan may underlie other as yet uncharacterised forms of muscular dystrophy and neuronal migration disorders.