Rapid ReviewDefective glycosylation in muscular dystrophy
Section snippets
Glycosylation defects and disease
Defects in glycosylation pathways in human disease were initially identified in 1980 by Jaeken et al following the observation of abnormal processing of thyroxin-binding globulin and arylsulphatase-A in patients with psychomotor retardation.6 Thirteen congenital disorders of glycosylation (CDGs) have been identified to date and they almost invariably affect N-glycan assembly (CDG type I) or processing (CDG type II).7 Common features of patients with CDG include varying combinations of
The role of α-dystroglycan
α-dystroglycan is a peripheral membrane component of the dystrophin-glycoprotein complex (DGC) common to several tissues including muscle, nerve, heart, and brain.9, 10 In muscle, this complex functions by linking the actinassociated cytoskeleton of the muscle fibre to the extracellular matrix via dystrophin and the laminin α2 chain of merosin (figure). The DGC is disrupted in several different forms of muscular dystrophy.11 Mutations in dystrophin cause Duchenne and Becker muscular
Glycosyltransferases and CMD (panel)
Condition Gene Protein function Clinical features Muscle α-dystroglycan Muscle-eye-brain disease (MEB) POMGnT1 O-mannosyl glycan synthesis Severe muscle weakness Absent on IHC and western blot* Mental retardation Epilepsy Neuronal migration disorder Ocular abnormalities Fukuyama congenital muscular dystrophy Fukutin Putative glycosyl-transferase Severe proximal and axial weakness Mental retardation Absent on IHC and western blot
Recent advances
The association of abnormal glycosylation of α-dystroglycan with muscular dystrophy has now been confirmed and extended by work originating from Kevin Campbell's laboratory.25, 26 Using a new antibody raised against a non-glycosylated portion of the molecule, α-dystroglycan was shown to be present in MEB, FCMD, and the myd mouse, but in a hypoglycosylated form that leads to loss of immunoreactivity with the antibodies used in the earlier studies.25 Furthermore, these investigators showed a
Future directions
Several forms of muscular dystrophy have now been shown to be due to defects in glycosyltransferases, abnormalities in which give rise to multisystem disorders. The precise substrates of these enzymes have yet to be fully determined. The glycosylation of α-dystroglycan in both muscle and brain appears to have an essential role in these conditions and sheds further light on the pathophysiology of muscle survival and neuronal migration. However, other muscle glycoproteins might also be affected
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