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RNA interference therapy heals growth deficiency disorder in a live animal
Date:12/18/2007

HD-II is what geneticists call a dominant negative disorder. It is caused by a defective form of human growth hormone that not only cant stimulate growth itself but also blocks the action of normal growth hormone. It acts like Aesops dog in the manger which has no use for the hay but keeps the cows from eating, says Phillips. Some other common dominant negative diseases include forms of colon cancer, deafness, muscular dystrophy, brittle bone disease, kidney disease and retinitis pigmentosa.

The blueprint for a protein like growth hormone is genetically encoded in a series of special segments called exons. The instructions in the exons are first copied onto a length of special RNA, called messenger-RNA. The messenger-RNA is moved to a structure in the cell called a ribosome, which links amino acids together in the order specified by the RNA sequence to create the protein.

Normal growth hormone is produced by a series of five exons. The defective hormone is the result of a splicing error: It is made by combining the segments coded by the first two exons and the last two exons, mistakenly skipping the third exon.

A normal person has a very small amount of this defective hormone about 1 percent but people in families with IGHD-II produce 10 to 20 to 50 percent. And the more they make the slower they grow, says Patton.

In 2003, co-author Iain Robinson at the National Institute for Medical Research in London created a transgenic mouse with the human growth hormone gene that duplicated growth hormone deficiency. Although the altered mice still contained the mouse growth hormone genes, he found that high levels of the defective human growth hormone not only stunted their growth but actually killed the cells in the pituitary that produce growth hormone.

This came as a real surprise: We never thought that a splicing error would lead to cell death, says Patton.

Meanwhile, progress in RNA interference research gave Patton and Phillips an idea for a w
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Contact: David F. Salisbury
david.salisbury@vanderbilt.edu
615-343-6803
Vanderbilt University  
Source:Eurekalert

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