Adult Muscular Dystrophy Linked to Protein "Stuttering"

A misstep in the production of a protein key to proper muscle function causes a major symptom of myotonic dystrophy, the most common form of adult onset muscular dystrophy, said researchers at Baylor College of Medicine in a report in the July 15 issue of the journal Molecular Cell.

Thomas A. Cooper, M.D., and colleagues found a glitch in one of the mechanisms that regulates the translation of genetic information into proteins. The mutation that causes myotonic dystrophy is a kind of regional "stuttering" that occurs as the gene is copied, creating repeats of a small region within the gene. This repeated sequence is an unusual kind of mutation. How this mutation causes disease is even more unusual. When the gene is "turned on" and copied into RNA, the repeated sequence causes the aggregation of the RNA in the cell nucleus, disrupting the functions of some other genes. The abnormal behavior of these other genes is what causes the disease.

The new results show that one of the genes affected tells the cell to make a particular chloride channel that is key to the proper functioning of muscle cells. This gene is effectively "turned off" in myotonic dystrophy muscle. As a result, the muscles still contract but have a reduced ability to relax. This is called myotonia, a major symptom for which the disease was named.

"This is a new mechanism for genetic disease in humans that could play a role in other disorders," said Cooper, an associate professor in the departments of pathology and molecular and cellular biology at Baylor.

The key to the new mechanism that causes genetic disease in humans is a process called alternative splicing. Humans are believed to have approximately 30,000 genes. However, there are at least 100,000 proteins key to the proper functioning of cells in different parts of the body.

"Obviously, some genes generate more than one protein," said Nicolas Charlet-Berguerand, a graduate student in Cooper’s lab. The genes do this by including or excluding portions of the genetic message. For example, a gene may cause one protein to be formed early in a tissue’s development and another protein to form later in life.

In this case, the regulation of alternative splicing is faulty and the genetic message for the protein is made incorrectly, causing the cell’s error-correcting mechanism to degrade it.

As a result, the chloride channel that should be present in the cell’s membrane is not formed and the muscle cells are unable to relax on key.

"As you try to relax that muscle, you keep getting contractions because the muscle membrane is unstable," said Cooper.

Cooper and his team that also included research associates Rajesh S. Savkur, Gopal Singh, Anne V. Philips, and Elizabeth A. Grice, did their work using tissues obtained from patients. A companion paper in the same issue of the journal by a team led by Charles A. Thornton, M.D., of the department of neurology at the University of Rochester in New York confirmed the findings in a model for the disease developed in mice.

---

©2006 Texas Medical Center

---

E-Mail: tmcinfo@texmedctr.tmc.edu
URL: http://www.tmc.edu/tmcnews/08_01_02/page_08.html