New Mouse Model Gives Clue To Muscle-wasting In Myotonic Dystrophy Type 1

Dr. Thomas C. Cooper and his colleagues from BCM and France described the new mouse in a report in the current online issue of the Proceedings of the National Academy of Science. Unlike previous mouse models of the disease, these animals have a genetic mutation that causes the muscle wasting that is the most devastating element of this inherited disorder, said Cooper, professor of pathology and molecular and cellular biology at BCM.

Genetic disease

Myotonic dystrophy occurs in as many as 1 in 8,000 people worldwide. Type 1 is by far the most common form. The most obvious symptoms are muscle wasting and weakness that can become life threatening. It is a genetic disease and can be inherited.

"We made our mutation as close to that which appears in people as is possible," said Cooper.

The mutation that causes muscular dystrophy involves a larger than normal series of repeats of the nucleotides C (cytosine), T (thymine) and G (guanine) in the end of the DMPK (dystrophia myotonica-protein kinase) gene. These large repeats make the product of the mutated DMPK gene toxic to cells.

Cooper and his colleagues made sure that the nucleotide repeats in the mouse gene occurred in the same area as the repeats in the human gene.

In this mouse, Cooper and his colleagues made the gene so that it remained dormant until the mouse reached adulthood. Then, when they turned it on, it caused rapid muscle wasting in as little as four weeks.

Alternative slicing

In studying the molecular attributes of these mice, Cooper and his colleagues found many features similar to those of people with the human form of myotonic dystrophy type 1. In this case, Cooper and his colleagues found alternative slicing events related to the CUG binding protein (CUGBP1), which has been previously shown important in myotonic dystrophy.

Alternative splicing is a key method by which the 25,000 to 30,000 human genes make the 100,000 or more proteins important to the functioning of the human body. For one gene to make different proteins, it has to alter the genetic message, choosing which coding parts of the gene called introns are included in the protein "recipe" used by the cell's protein-making machinery. In these mice, a mistake in the regulation of these alternative splicing events results in increased levels of the CUGBP1 protein, which indicates that this protein may play a role in the muscle wasting found in patients with myotonic dystrophy.

"This experiment tells us something about the different components in the mutation that you need to reproduce muscle wasting," said Cooper. "One of the subtle things we found in our mouse model is that there is a change in the expression of this one protein – the CUGBP1 protein – that is not seen in other mouse models. We found some genes regulated by this protein at the level of splicing and three of them were not regulated properly. When we looked at human patient samples, we saw that these three genes were also misregulated at the level of splicing. It looks as though our model is reproducing the events of the human disease."

Others who took part in this research include James P. Orengo and Drs. Dennis R. Mosier and G. Jackson Snipes of BCM and Pierre Chambon and Daniel Metzger of the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France.

Funding for this work came from the National Institutes of Health, the Muscular Dystrophy Association and the U.S. Department of Veterans Affairs.