The LARGE Gene Plays a Key Role in the Development of Muscular Dystrophy

It encodes a glycosyltransferase that participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. Mutations in this gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan.

The investigators reported in the January 6, 2012, issue of the journal Science that LARGE had two specific sugar-adding functions. The enzyme transferred the sugars xylose and glucuronic acid to molecules of dystroglycan. Dystroglycan is a protein precursor that yields a 43-kDa trans-membrane glycoprotein and an extracellular 156 kDa dystrophin-associated glycoprotein in skeletal muscle. The 156-kDa component binds laminin, acting as a laminin receptor that links the extracellular matrix and sarcolemma in skeletal muscle. Increasing LARGE activity in cells from patients with several types of muscular dystrophies was sufficient to restore dystroglycan function and overcome the defects in the cells.

“LARGE is a critical enzyme involved in maintaining muscle cell viability,” said senior author Dr. Kevin Campbell, professor of molecular physiology and biophysics at the University of Iowa. “It adds on a unique sugar chain that allows the muscle cell to protect its membrane from injury. By figuring out the function of this enzyme we have finally identified this critical sugar link.”

The insights regarding LARGE function gathered in this study have led to the development of an assay to monitor its activity. “It is exciting that we now have this enzyme assay, which could be used in a large-scale high-throughput screen for drugs that increase (or decrease) LARGE activity,” said Dr. Campbell.

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