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NEUROLOGY Faulty Membrane Repair May Lead To Muscular Dystrophy The muscular dystrophies are an idiosyncratic bunch, each striking at a preferred time and place in the body. Despite their peculiarities, they carry the same grim prognosis: a steady wasting away of the muscles. Efforts to uncover the roots of the disease were rewarded in 1986 when HMS researcher Louis Kunkel uncovered a mutated gene in patients suffering from one of the most severe forms of the disease, Duchenne's muscular dystrophy. Defects in the dystrophin gene render the muscle cell wall weaker and more susceptible to collapse in Duchenne's patients, and it was believed that structural defects in the cell membrane might be responsible for the other muscular dystrophies Muscular dystrophy may result when muscle cells lose their ability to repair everyday wear and tear on their membranes. Normally, when a cell membrane is damaged, intracellular vesicles travel to the site of injury where they form a kind of protective patch. Dysferlin, which binds the annexins, may help guide the vesicle patch to the site of injury. Defects in dysferlin, which have been found in people with some forms of muscular dystrophy, could therefore lead to disease by preventing injury repair. It now appears that the muscular dystrophies can arrive at their muscle-whittling goal by another route. Niall Lennon, Robert Brown, and their colleagues report that a genetic mutation found in people with either of two forms of the disease, limb girdle muscular dystrophy type 2B and Miyoshi myopathy, appears to cause disease by impeding the muscle cell's efforts to fix the everyday wear and tear that even healthy membranes experience. "This would, over time, lead to more muscle cells dying," said Lennon, HMS research fellow in neurology at Massachusetts General Hospital. The report, appearing in the Dec. 12 Journal of Biological Chemistry, "discloses a new pathway for the genesis of muscular dystrophy--that is, a failure of muscle repair," said Brown, HMS professor of neurology at MGH. "This has been very exciting for us." The discovery suggests that some forms of muscular dystrophy may be averted by boosting the muscle cells' ability to repair their membranes. The Genetic Puzzle Brown and his colleagues have been looking for ways to avert the damage caused by muscular dystrophy for nearly 15 years--ever since they were approached by a family with two sons suffering from an unknown form of the disease. With support from the family, and in collaboration with researchers abroad, Brown and his colleagues found that a defect in the dysferlin gene was responsible for limb girdle muscular dystrophy, which initially affects the upper arms and legs, and Miyoshi myopathy, which affects the calves. The two brothers carried abnormal dysferlin protein. But the researchers were intrigued: how did defects in dysferlin produce both the Myoshi and limb girdle disease patterns? The report "discloses a new pathway for the genesis of muscular dystrophy--that is, a failure of muscle repair." --Robert Brown Though little was known about the function of dysferlin, Brown and Lennon thought it might play a role in muscle cell membrane repair. To get a better sense of what it does, the researchers compared gene expression patterns from normal mice and mice carrying the dysferlin mutation. Working with Kunkel, HMS professor of pediatrics at Children's, the MGH researchers used a special program called Relevance Network Analysis to tease out 78 genes that seemed to be affected by the dysferlin lesion. Two genes, annexin 1 and annexin 2, were associated with membrane repair. Following that lead, Lennon and his colleagues performed co-immunoprecipitation, colocalization, and other experiments, all of which pointed to the same result, namely that the dysferlin protein interacts with the two annexins. To see if the trio did, in fact, play a role in muscle cell repair, the researchers injured muscle cells from normal and mutant mice. The normal cells repaired in a matter of seconds while the mutant cells took much longer. Patch Work It is still not clear how dysferlin, along with the annexins, helps cells repair damage. "When you have a rip in the membrane, you get this Band-Aid response--cells produce a patch-fusion response," said Lennon. The Band-Aid, in this case, appears to be made up of intracellular vesicles that fuse and travel to the injury, covering it and preventing vital cellular molecules from leaving or toxic ones from entering. One possibility is that dysferlin binds the annexins to bring the vesicle patch to the site of the breach. "This is still speculative, and we do not have a time course for this yet," he said. As for their original question--How does abnormal dysferlin produce both Myoshi myopathy and limb girdle muscular dystrophy in patients?--that, too, is open to future scrutiny. "This took us a little afield of that question," said Lennon. --Misia Landau