UNC-CH Scientists Link Mutation To Milder Forms Of Cystic Fibrosis

August 21, 1997

UNC-CH News Services

CHAPEL HILL -- An alteration in the gene that causes cystic fibrosis may be the culprit in certain other chronic lung and sinus infections as well, according to University of North Carolina at Chapel Hill School of Medicine researchers.

"The molecular basis for this genetic mutation -- and I use the term 'mutation' loosely here -- is called the 5T allele, and it appears normally in 10 percent of the population," said Kenneth Friedman, doctoral student in UNC-CH's Curriculum in Genetics and Molecular Biology. "Until recently, the 5T allele was thought to be harmless."

Further research showed that the 5T allele was six times more common in infertile men, Friedman said. Although the men didn't have cystic fibrosis (CF), they exhibited the same urological abnormalities as men with the illness, 99 percent of whom are infertile.

The question then became: If the 5T allele can cause one isolated feature of the greater CF disease picture such as infertility, might it not also be associated with other aspects of CF-like disease?

To find out, the UNC-CH researchers tested a huge data base of DNA samples available at the School of Medicine's Cystic Fibrosis Center. Their findings appear in the August issue of the journal "Human Mutation." Besides Friedman, co-authors of the report are Drs. Lawrence M. Silverman and Michael R. Knowles, professors of pathology and medicine, respectively.

"For many patients with mild sinopulmonary disease, we had never found CF gene mutations after we'd looked in all the typical places," Friedman said. "But when we tested their DNA samples for the presence of the 5T allele, it turned out that the frequency jumped nearly 3-fold. It's more common among a mixed bag of patients with obscure, hard-to-define lung and sinus diseases than in the general population."

Individuals with the 5T allele, whether they inherit two copies of the 5T allele or the 5T and a serious CF mutation on the other chromosome, aren't getting diagnosed anywhere near as early as the typical CF patient, he said.

"Like CF patients, they may have elevated sweat chloride values (salty sweat), but their levels aren't nearly as high," he said. "They may get infections later in life and can be treated with the same antibiotics as CF patients. In most aspects, they seem to exhibit some sort of milder form of CF."

No longitudinal studies have been done yet on patients with the 5T allele, Friedman said, so it's not possible to predict the disease's future course.

"The next questions to ask are: 'Who are the people who came up positive for the 5T allele?'" he said. "What do they have in common? For which clinical syndromes does 5T represent a genuine risk? If we can find out what these people have in common in terms of disease then we can do a study where we solicit patients with those clinical features and see what the 5T allele frequency is among them."

Sinusitis seems to be a significant feature of this milder form of cystic fibrosis, the researcher said. "That's not to say that people with sinus headaches and allergies should think they have mutations of the CF gene. That's just not true. It's just that sinusitis can arise from numerous causes, and one of them might be having the 5T allele.

"None of this represents proof," he said. "It's an association. The more powerful the association -- the stronger the statistics -- the more likely it is that the 5T mutation is the actual cause underlying some milder form of cystic fibrosis."

Cystic fibrosis is the most common fatal genetic illness among whites. Both men and women can inherit the ailment, and about one in 2,500 whites are born with it. The median age of survival is 30. The CF gene was cloned in 1989.

The Cystic Fibrosis Foundation and the N.C. Biotechnology Center support the continuing research.

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Note: Friedman can be reached at (919) 966-0713.

Contact: David Williamson

University of North Carolina at Chapel Hill

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