A reversible mouse model of myotonic dystrophy, the most common form of muscular dystrophy in adults, is reported in a study to be published in the September 2006 issue of Nature Genetics. The mouse model shows for the first time that at least some aspects of the disease might be fully reversible, and suggests that a potential therapy might be devised by targeting a particular kind of toxic molecule present in the diseased muscle.
Myotonic dystrophy occurs because of a large expansion in the number of 'CTG' repeats in a region flanking a gene called DMPK, and is associated with skeletal muscle loss, cardiac abnormalities, cataracts and insulin resistance. While there has been good evidence in favor of the idea that the expanded DMPK messenger RNA is toxic to cells in which it is expressed, and is the underlying cause of the disease, a definitive demonstration has been lacking. Mani Mahadevan and colleagues at the University of Virginia generated a mouse carrying an extra normal copy of the DMPK gene that could be turned on and off by adding (or removing) an antibiotic to the drinking water. Mice that expressed very high levels of this extra DMPK -- and thus had more copies of the CTG repeat -- showed all of the cardinal features of myotonic dystrophy. When expression of DMPK was turned off, normal skeletal and cardiac muscle function was restored in many of the mice. These results suggest that muscle damage in individuals with the disease might not be permanent, and that eliminating messenger RNAs carrying the extra CTG repeats might have therapeutic benefit.
Mani Mahadevan (University of Virginia, Charlottesville, USA)
Ramesh Yadava (University of Virginia, Charlottesville, USA)
Additional contact for comment on paper:
Lubov Timchenko (Baylor College of Medicine, Houston, TX, USA)
Abstract available online.
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