CF: maxi-mutations make mini-diseases.

CF: Maxi-mutations make mini-diseases

Since last year's discovery of the gene causing cystic fibrosis (cf), researchers have learned that several different mutations in this "CFTR" gene can cause the inherited respiratory disease. Now, to their surprise, they find that some of the most severe mutations cause the mildest forms of the illness.

The odd revelation, which suggests that some patients with minor CFTR mutations might be better off with a completely botched gene, provides fresh clues about CFTR's normal function. It also hints at the possibility of treating some cystic fibrosis cases by knocking out the faulty gene's activity rather than by correcting it through gene therapy.

Normal CFTR genes direct the production of a protein that helps ions cross cell membranes. Most CF patients lack three DNA subunits in the gene and make a slightly gimpy CFTR protein lacking only one amino acid. The ensuing ion-transport deficiency leads to an accumulation of mucus in the respiratory tract and repeated lung infections that leave few CF patients surviving their 30s.

In the latest work, presented this week at an American Society of Human Genetics meeting in Cincinnati, several research teams catalogued some of the less common CFTR mutations and correlated them with clinical symptoms.

Garry R. Cutting of the Johns Hopkins School of Medicine in Baltimore and his colleagues identified two CF patients with "nonsense mutations," which appear to block the synthesis of the CFTR protein. Nonsense mutations in other genes often cause severe illnesses, but the two CF patients (aged 11 and 22) remain remarkably healthy with only very mild pulmonary disease.

In a separate study, Edward Highsmith Jr. and his co-workers at the University of North Carolina School of Medicine in Chapel Hill looked at three other CF patients with similarly severe mutations. These three cases "are extremely mild," says highsmith, who notes that two of the patients weren't even diagnosed with CF until they were in their 50s and 60s. He adds that Belgian researchers recently reported comparable findings in patients with radical CFTR mutations.

The unexpected correlations may indicate that the CFTR protein normally functions by intertwining with a group of other proteins, say Cutting, Highsmith and others. They suggest that the complex may work reasonably well when the CFTR protein is either missing or so deformed that it fails to interact with the other proteins, whereas a mild mutation that only slightly distorts the protein's shape may completely disrupt the ensemble's activity.

If this theory holds true, says Cutting, CF symptoms might best be reduced by simply "knocking out" the faulty gene or its protein product -- at least until gene therapy becomes practical. Highsmith adds that "it's easier to design a drug that inhibits a protein than it is to design a drug that tweaks a faulty protein back to normal." Both researchers say the novel approach of "finishing off" an already hobbled gene must await experimental proof of its value.

Michael Dean, a molecular biologist at the Nati onal Cancer Institute's research and development center in Frederick, Md., cautions that other genetic factors, as well as environmental variables, probably influence CF severity. At the Cincinnati meeting, he reported evidence that some severe CFTR mutations do cause severe disease.