Spotlight on Research for 2006

May 2006 (historical)

Scientists Discover Role of Genetic Mutation in Two Forms of MD

To ensure a supply of healthy muscle tissue, the body constantly undergoes a process of turnover, whereby it builds new muscle protein while degrading and ridding itself of the old. Scientists believe a malfunction of this process is behind certain types of muscular dystrophies (MD), a group of genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. New research supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases has uncovered a possible mechanism by which interference with one aspect of normal muscle turnover results in two forms of the disease: limb-girdle muscular dystrophy type 2H and sarcotubular myopathy.

Both forms are associated with a mutation in a gene called tripartite motif-containing protein 32 (TRIM32), which functions as an E3 ligase, a class of enzymes that specifically target cellular proteins for degradation. In other words, TRIM attaches a molecular flag (called ubiquitin) to proteins that need to be degraded, like a property developer might flag a building scheduled for demolition.

So far, the researchers don't know exactly what the TRIM mutation does in people with the disease. What they have shown is that TRIM interacts with the two major proteins in muscle called myosin and actin. They showed that TRIM binds to myosin and modifies actin. It is likely that disruption of this process affects muscle protein turnover.

Most of the muscular dystrophies involve too much turnover - too much degradation, says Melissa Spencer, Ph.D., recipient of a Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor bestowed by the U.S. government on outstanding scientists and engineers beginning their independent careers, and senior author of the study. "What we are learning is that in some muscular dystrophies, there is not enough turnover, so you get an accumulation and it causes cellular malfunction." That, she suspects, is the case for limb-girdle MD type 2H, characterized by weakness of the muscles of the shoulders and hips, and sarcotubular myopathy, a nonprogressive form of muscle disease that may cause a delay in motor milestones in children.

Prior to the recent study, which was published in the Journal of Molecular Biology, "no one had described the cellular function of TRIM32 nor its targets," says Spencer. By learning about the function of the protein, the researchers hope to gain an understanding of the mechanism of the disease so they can then develop drugs to treat it.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Kudryashova E, et al. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J Mol Biol 2005:354 (2):413-424.