Scientists Unravel How Gene Flaw Causes Muscular Dystrophy

July 23, 2002

            Scientists have made a key finding about the cause of the most common form of muscular dystrophy in adults, myotonic dystrophy. The research, published in the July 18 issue of the journal Molecular Cell by a team at the University of Rochester Medical Center, explains how a faulty gene stops the body from making a protein crucial for muscle control.

            The work confirms the discovery of a new way that a genetic mistake can harm the body, say physicians on the team that made the finding. While the research marks an important step forward for our understanding of myotonic dystrophy, the scientists say any new treatment for the disease is likely years away.

            “People with myotonic dystrophy should take heart. In just a few years we have gained a much better understanding of a process that up to a few years ago was a complete mystery. But there’s still a great deal more work to do,” says Charles Thornton, M.D., the neurologist who heads the research team. Thornton spoke about the work at an invited talk earlier this month at the 10th International Congress on Neuromuscular Diseases in Vancouver.

            Thornton, who is co-director of the university’s Neuromuscular Disease Center, specializes in the treatment of conditions like myotonic dystrophy, a disease marked by progressive muscle weakness. Patients’ muscles become steadily weaker and waste away, and their muscles become stiff and can’t relax properly. A typical early symptom is shaking someone’s hand, then not being able to relax one’s grip for several seconds. Currently there is no medication to halt the disease or improve symptoms. Doctors estimate that about 35,000 people in the United States have the disease.

            Ten years ago scientists discovered the genetic defect – a kind of molecular stutter – that causes myotonic dystrophy, but until now they haven’t been able to spell out exactly how the defect causes the disease.

            Thornton’s team discovered that the faulty gene creates a product, messenger RNA or mRNA, that prevents a key molecular component from being made in muscles. The errant mRNA prevents a separate gene from making a protein known as the chloride channel, which is vital to maintain the proper flow of electricity in muscles. Without the chloride channel, electrical signals in muscles stay “on” for too long, and muscle control becomes unstable – like when someone grasps another’s hand and can’t let go.

            The work highlights an oft-overlooked process in the body, the steps necessary for turning DNA into the working proteins that carry out crucial tasks in the body. After all, it’s defective or missing proteins – often caused by mistakes in our DNA – that cause most inherited human disease. The step from DNA to protein is a complex journey where a DNA sequence is converted to an mRNA molecule, which is snipped apart and pieced together before serving as instructions to make a protein.

            Two years ago Thornton’s team developed a mouse that mimics what happens in people with the disease. Then the team showed that the mRNA, long considered simply a way for a cell to move key genetic instructions, itself is responsible for the symptoms of myotonic dystrophy. Faulty messenger RNA – an amazing array of different kinds of mangled mRNA – accumulates in the nuclei of cells in muscles of patients with myotonic dystrophy; such accumulation of abnormal material in the nuclei of cells also plays a role in other neurological diseases, such as Huntington’s and Parkinson’s diseases.

            “Somehow the abnormal mRNA coming from the myotonic dystrophy gene builds up in the nucleus and prevents other RNAs from being spliced correctly. That is what causes this electrical misbehavior in patients with myotonic dystrophy,” says Thornton.

            “We believe this is the first example of an abnormal gene that has a harmful effect in the human body because the RNA that the gene produces is toxic. Bad RNA is the culprit and good RNA is the victim.”

            It’s a little bit like an injured base runner with a limp blocking the way of the speedster just behind on the bases who has the potential to score the winning run. No matter how fast and healthy the second runner is, that player won’t get to home plate with an injured runner blocking the way. In this case, even though the gene that creates the chloride channel is fine, the channel is not made because another molecule gets in the way. The result is that missing chloride channels cause muscle weakness and stiffness by playing havoc with electrical impulses.

            Doctors have known that a problem with the chloride channel causes a similar disease, myotonia congenita, where patients have stiffness and involuntary contraction in muscles. In that disease the gene that codes for the chloride channel is defective; scientists have been baffled by myotonic dystrophy, whose symptoms are so similar even though the chloride channel gene itself is fine. The new findings explain the similarities.

            Thornton’s team is now working on understanding the mRNA flaw more thoroughly, and how the defect might cause muscle weakness as well as stiffness. One of Thornton’s colleagues, Richard Moxley, is currently leading a study testing the effectiveness of a medication known as mexiletine for patients with myotonic dystrophy. The medicine, often used to treat heart arrhythmias, is also used to treat myotonia congenita.

            The project has been supported by the Muscular Dystrophy Association, the National Institutes of Health, and the Saunders Family Neuromuscular Research Fund, funded by Rochester businessman Phillip Saunders and his family.

            In addition to Thornton and Moxley, the research team included Ami Mankodi, Hong Jiang, and William J. Bowers of the University of Rochester Medical Center; Masanori P. Takahashi and Stephen C. Cannon of Harvard; and Carol L. Beck of Thomas Jefferson University. Also in the July 18 issue of Molecular Cell is a paper by a group led by Thomas A Cooper at Baylor College of Medicine which also addresses the abnormal mRNA splicing in patients with myotonic dystrophy.

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