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Defective protein explains different forms of muscular dystrophy


Scientists have identified a defective protein on the surface of some cells that may cause the diverse symptoms associated with two types of muscular dystrophy.

The discovery provides a starting point for new investigations of muscular dystrophy and could help improve prenatal diagnoses of the disease. The research may also lead to insights into how the brain develops and what goes wrong in neurological disorders.

Tissue-selective deletion of dystroglycan. View full

"As we better understand the molecular mechanisms of muscular dystrophy, we have better tools to develop strategies for treatments," says Kevin Campbell, a Howard Hughes Medical Institute researcher at The University of Iowa in Iowa City, who led the research. The findings were reported in two recent papers in Nature.

Both studies investigate a protein on cell surfaces called alpha-dystroglycan. One paper reveals the importance of the protein in muscular dystrophy, and the other study confirms that defects involving alpha-dystroglycan are sufficient to cause the disease.

The protein helps create a "meshwork that connects the inside of the cell to the outside, allowing the molecules to communicate," according to M. Elizabeth Ross of the Weill Medical College of Cornell University in New York, who wrote an accompanying article in Nature.

In the first paper, researchers determined that almost no sugars were attached to alpha-dystroglycan in muscular dystrophy patients. Without the sugars, they demonstrated, the protein could not function. Genes that can cause muscular dystrophy code for enzymes that add these sugars.

The study "set up the case that dystroglycan is involved but didn't prove that it's the only molecule," says Campbell, who worked on both papers.

The second team set out to see what happens when the protein is absent from cells. Mice with this mutation die before birth; in order to study the loss of protein in animals, the Iowa researchers created mouse mutants that expressed dystroglycan everywhere except in their brains.

The results effectively proved that dystroglycan is the critical molecule in the disorder: Its absence alone created abnormalities. The mutant mice had brain defects similar to those of patients with some forms of muscular dystrophy. Their muscles, where the protein still functioned properly, were unaffected.

In humans, muscular dystrophy takes several forms that are congenital, or evident at birth. Though relatively rare, these forms can cause death by adolescence. The disorder involves a severe shortening of muscles, which leads to joint problems.

Patients with the forms known as muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) may also suffer from seizures, vision problems, and mental retardation. Their brains, which show an abnormality known as cobblestone lissencephaly, have a characteristic 'bumpy' appearance.

The concurrence of muscular problems and lissencephaly has been a puzzle to researchers. The new studies used the known genetic origins of the diseases to investigate the physical changes and effectively solve the mystery. By utilizing the genetic information in humans and mouse models, notes Ross, the papers "describe a powerful 'full circle' of investigation."

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Michele, D.E. et al. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418, 417-422 (July 25, 2002).
Moore, S.A. et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418, 422-425 (July 25, 2002).
Ross, M.E. Neurobiology: Full circle to cobbled brain. Nature 418, 376-377 (July 25, 2002).

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