Researchers identify defect that causes rare muscular d...( place by acting like a molecular Velcr...)

place by acting like a molecular Velcro that binds individual cells to the extracellular matrix, providing a bridge critical for the physical integrity of muscle. In the most common form of muscular dystrophy, Duchenne muscular dystrophy, the dystrophin protein, which provides an anchorage inside the cell, is absent. In the dystrophies Campbell studied, the defect is in anchoring the cell to the extracellular matrix that surrounds it.

The researchers discovered that while the core dystroglycan protein is present on cell surfaces, it is missing distinctive sugar molecules that decorate the protein. The process of adding sugars to proteins, called glycosylation, is an important finishing step in the processing of many proteins and provides a distinctive marking that allows binding partners to recognize the proteins. "When the sugars are missing, it is like Velcro without the loops it cant stick," said Campbell. "As a result, the cells dont adhere properly to the extracellular matrix and are easily damaged." Campbell and his colleagues hypothesize that several genes defective in these rare forms of muscular dystrophy are involved in the biochemical pathway that leads to glycosylation of dystroglycan.

Additional evidence for the importance of dystroglycan glycosylation came when first author Daniel E. Michele, and his colleagues discovered that a commonly used mouse model of muscular dystrophy, called the myd mouse, also has a defect in the biochemical pathway that adds sugar molecules to the dystroglycan protein in muscle and brain. In addition to muscular dystrophy, this mouse had neuronal migration defects very similar to that seen in the patients Michele studied. The loss of the binding of dystroglycan to matrix disrupts anchoring sites at the surface of the brain that are crucial for normal neuronal migration. In human patients, this type of neuronal migration defect results in abnormal smoothing of the brain surface.

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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
24-Jul-2002

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