Drug Candidates Help Cells to Understand Nonsense Mutations

Two chemical compounds have been identified that are able to prevent the premature termination of DNA translation into protein that is caused by the presence of "nonsense mutations.”

These nonsense mutations cause the loss of vital proteins that can lead to deadly genetic disorders such as muscular dystrophy and ataxia telangiectasia (AT), a progressive neurological disease that strikes young children.

In the current study investigators at the University of California, Los Angeles (UCLA; USA) used AT as a model system to screen more than 34,000 chemical compounds for the ability to induce the cell's protein synthetic machinery to "read around" the nonsense mutation that prevents manufacture of the ATM protein, which is missing from the cells of children with the disease.

They reported in the September 28, 2009, edition of The Journal of Experimental Medicine that two compounds consistently induced functional ATM protein in ATM-deficient cells containing disease-causing nonsense mutations, as demonstrated by direct measurement of ATM protein, restored ATM kinase activity, and colony survival assays for cellular radiosensitivity. The two compounds also demonstrated a similar activity in mdx mouse-myotube cells carrying a nonsense mutation and induced significant amounts of dystrophin protein, the protein lacking in muscular dystrophy.

"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 senior author Dr. Richard Gatti, professor of pathology, laboratory medicine, and human genetics at UCLA. "These nonsense mutations cause the loss of vital proteins that can lead to deadly genetic disorders."

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