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The root of the most common type of adult-onset muscular dystrophy appears to be a form of genetic stuttering that blocks the action of key proteins in cells, researchers from the University of Florida and the University of Rochester report in this week鈥檚 issue of Science.

These proteins, which help muscle and eye cells mature, stick to warped copies of RNA molecules that build up in a cell鈥檚 nucleus. The scientists have now found that this prevents the proteins from working right. Normally, RNA acts as an intermediary in a molecular assembly line, transmitting information from DNA to trigger protein production.

The discovery helps answer a question that has long mystified researchers who study myotonic dystrophy: How can one gene mutation found in certain people with the disorder essentially cause the same cluster of symptoms found in others who have the disease 鈥� but who feature an entirely different gene mutation?

鈥淭hese two genes encode proteins that do completely different things,鈥� said Maurice Swanson, Ph.D., a professor of molecular genetics and microbiology at UF鈥檚 College of Medicine and the UF Genetics Institute. 鈥淭he puzzle was that patients who have myotonic dystrophy show very similar clinical features yet have affected genes that function in different biochemical pathways.鈥�

The inherited disorder, found in one out of every 8,000 people, causes skeletal muscles to lose the ability to relax once they contract. The muscles progressively weaken and eventually waste away. 鈥淚f you go to shake someone鈥檚 hand and you have myotonia, you have a problem releasing your grip,鈥� Swanson said. 鈥淧eople with myotonic dystrophy show a severe delay in muscle relaxation.鈥�

The disease also affects the heart muscle and is associated with irregular heart rhythms that can lead to sudden death, as well as cataracts, premature hair loss and mild to moderate mental retardation, according to the Muscular Dystrophy Association, which funded the research. Ongoing research is supported by the National Institutes of 网红黑料. These symptoms worsen with each generation as ever-increasing copies of a malfunctioning RNA repeat sequence are produced.

Normally, people have about five to 37 copies of the RNA repeat, Swanson said. Those with myotonic dystrophy have at least 50 repeats, and the most severely affected can feature more than 3,000. As the number of repeats expands, symptoms intensify.

鈥淭he reason the disease gets worse is this RNA expansion gets larger in each successive generation,鈥� Swanson said. 鈥淎 (woman) might have a premutation and display no overt disease symptoms, but her son or daughter might develop these unusual cataracts associated with myotonic dystrophy in their 30s and may develop severe muscle weakness as time goes on. The succeeding generation could be born with congenital myotonic dystrophy, with mental retardation and severe loss of muscle. These children are susceptible to respiratory failure.鈥�

UF and Rochester researchers studied more than 100 mice bred to lack the gene associated with producing one form of the so-called 鈥渕uscleblind鈥� protein. These mice, incapable of generating the protein, subsequently developed the muscle and eye abnormalities characteristic of myotonic dystrophy. They also developed other features associated with the disease, including cellular quirks such as abnormally positioned muscle nuclei and defects in proteins critical for normal heart function.

The mice did not display the full spectrum of symptoms seen in people with the disease, but researchers suspect other forms of the muscleblind protein must be rendered ineffective to spark the full constellation of problems. They鈥檒l work to test that hypotheses next, also in mice, said Swanson, who collaborated with other scientists from UF鈥檚 Powell Gene Therapy Center, including eye researcher William Hauswirth, Ph.D., and investigators at the University of Rochester鈥檚 School of Medicine and Dentistry, including neurologist Charles A. Thornton, M.D.

鈥淭here鈥檚 another group of proteins we work on that also are involved in causing myotonic dystrophy pathogenesis,鈥� said Tom Cooper, M.D., a pathologist who studies the condition at Baylor College of Medicine. 鈥淚t鈥檚 also important to figure out how these two sets of proteins are involved. So as usual it turns out to be a very complicated picture and not as straightforward as we鈥檇 like to think. That鈥檚 why it takes so long to go from a finding like this to something that really benefits patients.鈥�

UF and Rochester scientists discovered the existence of the muscleblind protein three years ago, after investigators at three separate institutions discovered the genes for the two forms of myotonic dystrophy in 1992 and 2001. Expanded sections of genetic material on chromosome 19 or chromosome 3 were implicated. Researchers haven鈥檛 been sure how these genetic expansions actually produce symptoms.

鈥淯sually when you find the mutation that causes a disease an understanding of how that mutation causes the disease kind of tumbles out,鈥� Cooper said. 鈥淏ut in this case investigators were still baffled even after knowing the nature of the mutation. It wasn鈥檛 clear how this mutation, particularly in the part of the gene it鈥檚 located in, could cause the disease. There were several different hypotheses that came out, all very different and all with very different implications. It takes studies like this to try to figure out which of those hypotheses is right and really go after what鈥檚 going on.

鈥淚 think it鈥檚 quite exciting,鈥� he added. 鈥淚t鈥檚 very strong evidence that the protein (Swanson is) working on, muscleblind, is involved in the pathogenesis of myotonic dystrophy. It makes the genetic connection between this protein and the disease. It鈥檚 not necessarily shown to be a direct connection yet, but the implications are very strong.鈥�

The discovery suggests that someday restoring normal levels of functioning muscleblind protein could prove to be an effective way of treating the muscle and eye problems associated with the disease, Swanson said. But researchers are years away from testing gene therapy in people with myotonic dystrophy.

鈥淚t鈥檚 an early step but more important it鈥檚 a big step,鈥� Cooper said. 鈥淵ou go from having many possibilities that are just a bunch of maybes to having your hand on something. Now we have a reagent that we can use 鈥� it鈥檚 not just an idea any more 鈥� that can be used to take the next step.鈥�