LARGE Role in Muscle Health

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Science  18 Jun 2004:
Vol. 304, Issue 5678, pp. 1719-1721
DOI: 10.1126/science.304.5678.1719e

Muscular dystrophy (MD) encompasses more than 30 distinct inherited disorders, all characterized by progressive muscle wasting. As new causative genes are identified, researchers continue to refine their mechanistic models of how MD arises. Several congenital forms of MD are caused by defects in genes encoding putative glycosyltransferases (enzymes that add sugar chains to proteins), and a key muscle protein called Δ-dystroglycan (Δ-DG), is hypoglycosylated in these disorders. One of these glycosyltransferases implicated in MD, LARGE, is the subject of two new studies. Barresi et al. find that overexpression of LARGE restores Δ-DG function in cells from patients with genetically distinct forms of congenital MD and prevents muscle degeneration in a mouse model. Kanagawa et al. reveal that Δ-DG glycosylation is LARGE-dependent and that disruption of the interaction between the two proteins leads to loss of Δ-DG function, ultimately causing muscle cell death. These results suggest that enhancement of LARGE activity may be a useful therapeutic approach for certain forms of MD. — PAK

Nature Med. 10.1038/nm1059 (2004); Cell 10.1016/S0092867404005434 (2004).

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