Myopathy: A genetic disease?

Researchers pin muscle disease to genetic mutation

September 15, 1998

A collaborative effort by researchers at the University of Chicago and a group from Barcelona, Spain has shown that a specific genetic deletion is responsible for one form of myopathy--a weakening of the heart and body muscle that often leads to heart failure and generalized muscle degeneration. The findings are reported in the September 15, 1998 issue of the Proceedings of the National Academy of Sciences.

"Though a group at the National Institutes of Health recently reported desmin mutations in several cases of generalized myopathies, our report now provides the first functional evidence to link a mutation in the desmin gene to this type of myopathy in humans," says Elaine Fuchs, Amgen Professor in the Departments of Molecular Genetics and Cell Biology and Howard Hughes Investigator at the University of Chicago, to determine if the mutation was in fact responsible for the defective muscle fibers. Fuchs is an internationally recognized authority on blistering diseases involving mutations in keratin, a skin protein belonging to the same family as desmin.

Although the condition is uncommon, this discovery makes possible genetic testing for couples concerned about passing the disease to their children because of histories of the disease in their families.

Myopathies are muscle diseases caused by abnormalities in the fibers that make up individual muscle cells. These fibers are essential for muscle contraction. In healthy cells, the fibers are organized into neat bundles packed end to end. When a muscle flexes or extends, the fibers slide past each other to shorten or lengthen the muscle. Small ratchet-like molecules lining these fibers lock them into place until the muscle relaxes.

In myopathy, the fibers are aggregated and cannot function properly, leading to a mechanical breakdown of the muscle with repeated exercise and movement. Because the heart is constantly active, people with these defects often die of heart failure.

In the fall of 1994 Spanish researchers discovered a genetic abnormality in a 28-year-old patient who died of respiratory failure after 9 years of progressive muscle weakness. When a sample of the patient's muscle tissue was observed under a microscope, it showed signs of degeneration, and the individual muscle filaments were disorganized. Preliminary genetic tests determined that a piece of the gene responsible for the protein desmin--a protein that forms a type of muscle filament--was missing.

The researchers sent a sample of the tissue and the results of their genetic testing to Fuchs.

"We agreed to collaborate in functional studies of this mutation and confirmed the results of the genetic tests," say Geraldine Strasser and Dr. Yanmin Tang, part of Fuchs' research ream.

The mutation caused the loss of seven amino acids from desmin. In order to confirm that this particular mutation was responsible for causing the muscle abnormalities observed in the patient, Fuchs' team engineered the defective protein in the laboratory and studied its behavior in cultured cells. Instead of assembling into desmin filaments, the protein formed disorganized clumps similar to those observed in the patient.

"The recreation of the disease in muscle cells transfected with the mutated gene leads us to believe that this deletion mutation is what causes this form of myopathy," says Fuchs.