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Researchers trace effects of genetic defect in myotonic muscular dystrophy
Date:1/24/2010

bnormal RNA prevents them from carrying out their normal functions in the cell. Mbnl1 is involved in a process called RNA splicing, in which the messenger RNA copied from a gene gets "edited" before it can direct the synthesis of proteins.

"When a gene is turned on, its DNA sequence gets copied into a messenger RNA molecule. But that direct copy needs to be processed to make a functional message that can be translated into a protein," Ares said. "Splicing factors like Mbnl1 tell the splicing machinery where to do the cutting and pasting. Without Mbnl1, incorrect splicing can affect lots of different genes."

Ares has pioneered the use of microarray technology to detect changes in RNA splicing caused by genetic mutations and other perturbations. UCSC graduate student Hongqing Du, the first author of the paper, earned her M.D. from Harbin Medical University in China and was eager to apply this technology to a human disease. So Ares and Du teamed up with leading investigators of mytonic dystrophy who had developed animal models of the disease.

Charles Thornton's lab at the University of Rochester School of Medicine developed a mouse strain that expresses large amounts of the abnormal repeat RNA in muscle cells. Maurice Swanson's lab at the University of Florida College of Medicine developed a mouse strain that is unable to make the Mbnl1 protein. Both strains of mice show symptoms similar to myotonic dystrophy.

Ares's lab used splicing-sensitive microarrays developed in collaboration with Affymetrix to show that the RNA splicing defects in muscle cells from these two mouse strains are nearly the same. This indicates that the vast majority of the splicing problems are due to the loss of the Mbnl1 protein as a result of binding to the abnormal repeat RNA. Earlier studies had associated several splicing defects with the disease, but the microarrays revealed effects on a much larger number of genes.

"Our microarray methods det
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Contact: Tim Stephens
stephens@ucsc.edu
831-459-2495
University of California - Santa Cruz
Source:Eurekalert

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