Cystic fibrosis gene and protein identified.

Cystic fibrosis gene and protein identified

After years of searching through DNA strands, a U.S.-Canadian research team has located the defective gene causing cystic fibrosis and has isolated its protein product. The finding might ultimately lead to new treatments and better genetic counseling for this devastating genetic disorder, which strikes one in every 2,000 white children in the United States.

"There has been an enormous bottle-neck in the understanding of cystic fibrosis, and that has been the failure to identify the gene," Francis S. Collins of the University of Michigan in Ann Arbor said last week at a press confrence in Washington, D.C. Collins and colleagues Lap-Chee Tsui and Jack R. Riordan of the University of Toronto will publish three scientific papers describing the mutant gene's exact location and protein product in the Sept. 8 SCIENCE.

"There is still a tremendous amount of work to do, but this is a major step forward," says Judith E. Fradkin of the National Institute of Diabetes and Digestive and Kidney Diseases.

Tsui narrowed the search to chromosome 7 in 1985, and the collaboration with Collins yielded a faster method of scanning DNA, enabling the tem to pinpoint the faulty gene in March. There they found a mutation resulting in a flawed protein that cause most, though not all, cystic fibrosis cases. The mutant gene's blueprint directs cells to produce a protein missing an amino acid called phenylalanine. "This error somehow changes the ability of the protein to work correctly in the cell," Collins says.

The protein belongs to a class of compounds normally involved in transporting ions, such as sodium and chloride, across cell membranes. Scientists believe cystic fibrosis patients have difficulty moving salt and water in and out of cells, leading to the secretion of thick mucus that clogs airways and leaves patients vulnerable to chronic lung infections.

Riordan says the work may eventually yield drugs that correct the flawed protein's action, thus alleviating the symptoms of cystic fibrosis. But before researchers can look for drugs to compensate for the defect, they must learn precisely how the flawed protein causes the disease, he adds. Alternatively, scientists may find a way to insert a normal gene into the cells of cystic fibrosis patients, directing the cells to manufacture a normal protein product.

Such breakthroughs remain distant, the scientists caution. "Human gene therapy is a new area of investigation, and many scientific, ethical and safety issues must be settled before trying such treatments," Collins says.

Doctors have no treatment now to correct the disease's underlying defect. Instead, they rely on physical therapy to clear away mucus and on antibiotics to combat lung infections. While that regimen has helped prolong lives, most people with cystic fibrosis die by age 30.

With the gene and its protein product identified, says Robert K. Dresing, president of the Cystic Fibrosis Foundation in Bethesda, Md., "we can finally look into the eyes of the children and young adults with cystic fibrosis and tell them that the door to their future has been opened." Dresing has a son with the disease.

In the near term, Collins and his colleagues predict development of a cystic fibrosis screening test for the general population. Currently, genetic counselors can give couples with a family history of cystic fibrosis an estimate of their risk of having a child with the disease, but they have no way to identify healthy carriers of the defective gene who have no such history. One out of 20 whites in the United States carriers this genetic flaw but has no symptoms of the disease. To get cystic fibrosis, a child must inherit a defective gene from each parent.

The research team hopes to find other mutations on the same gene within the next few months. At that point, they say, scientists could devise a highly accurate genetic test for cystic fibrosis, including a diagnostic test for fetuses. "A large public education effort will be needed to inform people about cystic fibrosis and enable them to make a rational decision about testing" and whether to abort an affected fetus, Collins says.