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Chemicals Prevent Premature Termination of Protein Synthesis in Genetic Disease

Using high-throughput screening of 35,000 compounds, scientists at UCLA have identified two compounds (nonaminoglycosides) that may have the potential to correct certain genetic diseases that are caused by the premature termination of protein synthesis due to nonsense mutations in the coding DNA. "When DNA changes, such as nonsense mutations, occur in the middle rather than the end of a protein-producing signal, they act like a stop sign that tells the cell to prematurely interrupt protein synthesis," explained Dr. Richard Gatti, senior author of the study. "These nonsense mutations cause the loss of vital proteins that can lead to deadly genetic disorders." Dr. Gatti's lab specializes in studying ataxia-telangiectasia (A-T), a progressive neurological disease that strikes young children, often killing them by their late teens or early 20s. "Of the dozens of active chemicals we discovered, only two were linked to the appearance and function of ATM, the protein missing from the cells of children with A-T," said Dr. Liutao Du, the first author of the study, in speaking about cellular studies that were conducted. "These two chemicals also induced the production of dystrophin, a protein that is missing in the cells of mice with a nonsense mutation in the muscular dystrophy gene." The UCLA team is optimistic that its discovery will aid pharmaceutical companies in creating drugs that correct genetic disorders caused by nonsense mutations. This could potentially affect one in five patients with most genetic diseases, including hundreds of thousands of people suffering from incurable diseases. Because nonsense mutations can lead to cancer, such drugs may also find uses in cancer treatment. This study was published in the September 28 issue of the Journal of Experimental Medicine. [Press release] [JEM abstract]