(12 Mar 1998 13:39 EST)

New Insight Into Cystic Fibrosis Protein NEW YORK (Reuters) -- The mutant protein responsible for up to 70% of cases of cystic fibrosis contains a mistake that changes the shape of the protein -- rendering it useless in those with the genetic disorder, according to a report in the March issue of Nature Structural Biology. If researchers can find a way to manipulate the protein into a functional state, they may have a treatment for cystic fibrosis (CF), an incurable disease caused by a malfunction of the chloride ion transport system in cells. ``This finding has important implications for understanding diseases resulting from protein misfolding and for developing new therapies,'' according to an editorial by Drs. Michael J. Welsh and Lynda S. Ostedgaard of the University of Iowa College of Medicine in Iowa City, Iowa. The disease is caused by a number of different defects in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel protein. The genetic defect results in abnormally high mucus production affecting mainly the lungs, pancreas and sweat glands, and CF patients are particularly prone to respiratory infections. People with cystic fibrosis actually make CFTR, but the protein becomes trapped inside a cell rather than traveling to its proper location on the cell surface, according to the study. Dr. Gergely L. Lukacs and colleagues at the University of Toronto, Ontario, Canada looked at F508, the mutated protein that causes 70% of CF cases. They found that a folding flaw is indeed to blame for the protein becoming trapped inside a cell, and that the mutant protein seems to be in an immature state. Instead of being ``exported'' to the cell surface, the mutant protein is retained inside the cell and ``subsequently degraded,'' according to the report. Welsh and Ostedgaard note that laboratory studies suggest that F508 functions almost normally if it reaches the cell's surface. And certain factors such as a lower temperature and chemicals like glycerol can help the molecule escape from the inner workings of the cell. ``Hypothermia and glycerol cocktails are probably not an option'' for treating patients, they note. ``But a search for more feasible pharmacologic interventions may prove worthwhile.'' SOURCE: Nature Structural Biology (1998;5:167-169, 180-183) Reut13:39 03-12-98

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