Alternate Gene May Help in Muscular Dystrophy

The utrophin gene, if overexpressed, may be able to substitute for the missing dystrophin gene and at least partially alleviate the symptoms of Duchenne's muscular dystrophy (DMD). Duchenne's muscular dystrophy is one of the most frequent hereditary diseases of men, affecting one in 3,500 boys. It occurs when the dystrophin gene, located on the short arm of the X chromosome, is nonfunctional. Without the dystrophin protein, muscle tissues cannot tolerate the stress of contraction and relaxation sufficiently and eventually break down.

As an alternative to gene therapy to replace the missing dystrophin, scientists have been investigating the utrophin gene. This gene is found in several types of tissue, and its protein product functions similarly to dystrophin protein. However, the utrophin protein does not function as well as the dsytrophin protein, nor is it present in as high a concentration.

In a report in the May 15, 2002, issue of the Journal of Neurological Sciences, researchers at the University of Pennsylvania School of Medicine (Philadelphia, USA) detail the cellular mechanisms that promote and regulate the transcription of the utrophin gene into protein. Their findings may help to design drugs that will produce excess utrophin in people suffering from DMD and help to compensate for the missing dystrophin protein.

"Utrophin has been a major focus in muscular dystrophy. Dystrophin and utrophin perform similar tasks at the neuromuscular junction – where nerve cells meet muscle tissue – and studies have shown that utrophin over-production reverses the symptoms of muscular dystrophy in mice,” said Dr. Tejvir S. Khurana. "Over-production of utrophin may be a viable alternative to adding a working copy of the dystrophin gene through gene therapy,” said Dr. Khurana. "The available research supports the idea that if you can crank up the production of utrophin, you will compensate for the lack of dystrophin.”

The mechanism for transcriptional regulation of utrophin is quite complex and not yet completely understood, but the researchers did demonstrate promotion of utrophin in response to heregulin and transcription factor Sp1. This work was carried out in Drosophila S2 cells.
"These findings will help define targets for stimulating the muscle cells' native mechanisms into producing more utrophin,” added Dr. Khurana. "And while a substitute isn't always as good as the original, in this case good enough may well result in a substantial improvement.”



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