The findings, which help explain the wide range of signs and symptoms associated with the disease, appear in the Dec. 4 issue of Science Express, the advance online edition of the journal Science.
“Typically in genetic diseases, a mutation affects a single protein, resulting in a predictable range of findings,” explains physician-investigator and senior author Richard Junghans, M.D., Ph.D., of the Division of Hematology-Oncology at BIDMC. “In contrast, it has become clear over the past several years that no such simple explanation could account for myotonic dystrophy, which exhibits diverse effects, not only in the muscles, but in many other organs as well.”
The study’s new findings show that the single genetic flaw of MMD can concurrently disturb many proteins in cells throughout the body. This, says Junghans, could potentially underlie such symptoms as muscle weakness, myotonia (difficulty relaxing muscles), premature balding, cataracts, digestive and gynecological abnormalities, heartbeat irregularities and mild to moderate neurological dysfunction. The defect that causes MMD – an abnormally large section of DNA on chromosome 19 – was first identified in 1992, when it was discovered that this mutation leads to the production of mutant RNA (ribonucleic acid) in cells throughout the body. The new findings by Junghans and postdoctoral researcher Alexander Ebralidze, Ph.D., take things one step further.
The authors show that in MMD-affected cells, mutant RNA binds to and interferes with the cells’ transcription factors, causing them to become trapped and prohibiting them from “reading” DNA’s genetic instructions. As a result, cells are unable to manufacture normal amounts of specific proteins necessary for proper functioning, leading to the development of MMD.
“Proteins are at the center of the health of all cells,” explains Junghans. “The trapped transcription factors seen in MMD patients result in less-than-adequate protein production in affected tissues of the body,” he adds, noting that this is the first time that abnormal RNA has been shown to adhere to transcription factors and inhibit the normal cellular protein manufacturing process. The investigators also showed that a depressed protein in MMD-affected cells could be restored to normal by adding back extra transcription factor, suggesting a means to correct unhealthy cells.
“There’s a unifying appeal to this discovery, if it ultimately proves to be the primary mechanism of the disease,” Junghans notes. “This new mechanism would cause multi-gene, multi-protein defects from a single ‘mutation,’ which could potentially explain the multi-system abnormalities we see in clinical cases of MMD.
“When we better understand which of the affected transcription factors are most critical, it may be possible to give back extra transcription factors via gene therapy, thereby restoring proper synthesis for many proteins simultaneously,” he adds. “One hopes this would also restore the health of muscle and other affected tissues in MMD patients.”
In addition to Junghans and Ebralidze, coauthors include BIDMC scientists Yawen Wang, Ph.D.; Victoria Petkova, Ph.D.; and Konstantin Ebralidse, Ph.D.
This study was funded by grants from the Muscular Dystrophy Association and the National Institute for Arthritis, Muscle and Skin Diseases (NIAMS) of the National Institutes of Health.