Egg of toad and cell of bug provided some cool clues in one ofthe latest attempts to track the cause, and a possible cure, ofcystic fibrosis (CF).

When researcher Michael J. Welsh and his associates at theUniversity of Iowa College of Medicine went looking atprevious experiments, they were surprised by one finding.Efforts to express the main mutant CF protein in the oocytes ofXenopus laevis, the African clawed toad and in insect cellsresulted in aberrant proteins that functioned almost likenormal, healthy proteins. The why had everything to do withtemperature.

The protein that CF distorts is a plasma-membrane chloridechannel called cystic fibrosis transmembrane conductanceregulator (CFTR). It regulates the flow of chloride ions into andout of epithelial cells. It is the blocking of this ion traffic bymutant CFTR that clogs the lungs, intestines and reproductiveorgans of CF sufferers with thick mucus.

In most CF cases, the mutant chloride-channel protein lacks asingle amino acid, and that's the aberration that appears toprevent the protein from exiting the endoplasmic reticulum(ER). Entrapment in the ER can be overcome by lowering thetemperature of cells being studied.

The Iowans, jointly with investigators at Genzyme Corp. ofCambridge, Mass., expressed mutant CFTR proteins in a range ofother cells and found that when they cooled them a fewdegrees below body temperature, the proteins behaved likethose from the path-finding toads. The cold-blooded reptilescoolly released the mutant CFTR proteins from the ER anddelivered them to their appointed places on the cell surface.Welsh's group reported this temperature-sensitive finding inlast week's edition Nature

"It is difficult to imagine any clinically acceptable therapeuticapproach based on significant, repeated reduction in whole-body temperature," they wrote. Noting that lung disease is theprincipal cause of death in CF patients, they suggested thatcold-air inhalations might beneficially alter the cellularprocessing of mutant CFTR.

"Therapy is far from the purpose of our temperature-sensitivity findings," Gerene M. Denning, a biochemist and thepaper's principal author, told BioWorld. "Our studies indicate aprotein-folding defect in the mutant CFTR, and show that weare heading in the right research direction."

The effort is directed at developing a way to detect "CFTR atthe plasma membrane, so that we may screen candidate drugsto see which if any can correct the mutant defect," she said.

-- David Leff Science Editor

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