P.8.2 Reduction of LARGE expression in different types of muscular dystrophies other than dystroglycanopathy

Abstract

Mutations in the genes coding for putative or demonstrated glycosyltransferases or other proteins involved in alpha-dystroglycan (ADG) glycosylation pathway result in the failure of alpha-dystroglycan to be properly glycosylated and lead to genetic forms of muscular dystrophy, collectively termed as dystroglycanopathies. An important enzyme which is involved in maintaining muscle cell viability, known as LARGE, has been shown to participate in O-mannosyl phosphorylation of ADG. It could also act as a bifunctional glycosyltransferase and allow ADG to bind laminin-G domain containing ligands. Additionally, transient overexpression of LARGE enzyme demonstrated a marked increase in hyperglycosylation of ADG and a corresponding increase in high affinity binding to several extracellular matrix ligands. To date, it has not been investigated whether LARGE enzyme affects the basic pathogenic mechanisms of muscular dystrophies, except for dystroglycanopathies and the influence of LARGE gene expression in different types of muscular dystrophies is not known. In this study, the expression level of LARGE and ADG immunofluorescence were examined in skeletal muscle biopsies from 26 patients with different forms of muscular dystrophy (i.e. DMD, BMD, calpainopathy, sarcoglycanopathy, dysferlinopathy, and merosin and collagen VI deficient CMDs) and correlation with different histopathological findings was investigated. We detected reduced expression level of LARGE gene in different types of muscular dystrophies, partly correlating with the severity of dystrophic changes, but we did not find any significant relationship between reduction of LARGE expression and ADG hypoglycosylation. Our results suggest that LARGE enzyme might have another function in skeletal muscle fibers that is probably distinct from adding a critical sugar chain onto ADG.