Defective glycosylation in muscular dystrophy

Context 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 α-dystroglycan, an external membrane protein expressed in muscle, brain, and other tissues, is a common feature in these disorders. α-dystroglycan is highly glycosylated, its sugar components varying in different tissues and controlling its interaction with extracellular matrix partners. Disrupted glycosylation of α-dystroglycan results in a loss of these interactions, giving rise to both progressive muscle degeneration and abnormal neuronal migration in the brain.