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Jackson Laboratory Researcher Explores Newly Discovered Form of Muscular Dystrophy

31 Mar 2006 - A Jackson Laboratory associate staff scientist has found a mouse model with a previously unknown genetic defect that causes a kind of muscular dystrophy (MD). The finding could shed light on some human MD cases for which a specific genetic link has not been established.
 
For many people, the term muscular dystrophy has become equated with Duchenne muscular dystrophy, the devastating sex-linked genetic disease that leads to the breakdown of muscles in children (mostly boys) and death as young adults. But while Duchenne muscular dystrophy is the most common form seen in humans, there are a variety of muscular dystrophies caused by different genetic disorders. All are characterized by defects in muscle proteins and increased muscle cell breakdown and death over time, but disease progression varies widely. Some, like Duchenne, are devastating and ultimately fatal, while others have relatively mild symptoms and no impact on lifespan.
 
Dr. Wayne Frankel, noticed a spontaneous mutation in his mouse colonies that led to abnormal forelimb development and severe progressive wasting of the hind limb muscles, with less muscle loss the closer one got to the head. The other major systems of these mice were generally unaffected. Dr. Gregory Cox of The Jackson Laboratory, an expert in mouse models of neuromuscular disease, began to research this unusual mouse model and soon discovered something quite unexpected. As it turned out, the mutation was not in a pathway implicated in known forms of MD.
 
"Instead," said Cox, "it's in a gene that codes for a protein, choline kinase beta, that is involved with cell membrane construction. It's one of two choline kinase enzymes involved with the synthesis of a major cell membrane component, phosphatidylcholine, that's found throughout the body. Choline kinase alpha mutations are likely to be embryonic lethal, but the beta mutation resulted in this muscular dystrophy."
 
The questions raised by this discovery are numerous and perplexing. If phosphatidylcholine is found throughout the body, why are only skeletal muscle cells affected, and why in such an odd back-to-front pattern? Why doesn't the mutation disrupt heart muscle tissue? How do the two kinases, alpha and beta, work together, and if you produce a lot more than usual of one, would that make up for not having the other? Does this form of the disease exist in humans? These are questions Cox is preparing to answer, with particular emphasis on the human element.
 
"We are working with Dr. Mayana Zatz, director of the Human Genome Research Center at the University of Sao Paulo, Brazil, who has a huge MD screening program there for both clinical and research purposes. They can currently identify about 75% of the MDs they see, but 25% don't involve known mutations, so we'll see if this mutation is present in some of those patients. At the same time we'll research possible therapeutic avenues using the mutant mice here in my lab. For example, we plan to see what happens when we add the gene back into the mice. Will we be able to stop the disease progression and keep the muscle cells healthy?"
 
The work promises to be rewarding regardless, but Cox readily expresses his hope that his unique mice are not just an isolated anomaly. Perhaps they will help to open up a window on the problem of muscular dystrophies of all kinds.