Cystic fibrosis gene: too many mutants.

Cystic fibrosis gene: Too many mutants

To their growing surprise and disappointment, researchers analyzing the CF gene in cystic fibrosis patients around the world have found dozens of different genetic mutations capable of causing the debilitating respiratory disease. Although each mutation reveals something new about the poorly understood genetic basis of cystic fibrosis (CF), the added complexity has geneticists scaling back their hopes for rapid development of a useful CF-screening test.

Last year, when researchers discovered the gene mutation responsible for most CF cases, they expressed hope that just a few other mutations in the CF gene might account for the remaining cases of this relatively common inherited disease (SN: 9/2/89, p.149). Instead, they've found more than 40 CF-causing mutations, and the number may grow.

That was unexpected, says Lap-Chee Tsui, the University of Toronto geneticist who co-discovered the CF gene. Tsui described some recent progress -- and several problems -- along the road to understanding and curing CF this week during the Short Course in Medical and Experimental Genetics held at the Jackson Laboratory in Bar Harbor, Maine.

Tsui said analysis of 13,000 chromosomes from people with mutated CF genes reveals striking racial and geographic differences. In Denmark, for example, 90 percent of CF mutations involve the loss of an amino acid, phenylalanine, at position 508 in the 1,480-amino-acid protein. This protein is made under the direction of the CF gene. In Israel, among Ashkenazic Jews and Arabs, only 30 percent of CF mutations involve this loss. There and elsewhere, other CF-causing mutations arise with characteristic frequency, and some evidence suggests different mutations may determine the disease's severity.

This genetic variability has slowed development of a prenatal screening test for CF, which, to be useful, must detect the vast majority of CF-causing mutations. However, the newly found mutations spotlight parts of the CF gene critical to its function. That information might open the door to new drugs or genetic therapies.

Along these lines, an analysis of four new CF mutations, described by Tsui and others in the July 26 NATURE, lends support to the theory that the CF protein plays a role in shuttling chloride ions across cell membranes.

The research, led by Garry R. Cutting at the Johns Hopkins University School of Medicine in Baltimore, suggests to some that the CF protein regulates the activity of protein-lined "channels" that grant chloride ions access through cell membranes.

Tsui says researchers wishing to investigate the CF protein remain hampered by their inability to coax genetically engineered bacteria or mammalian cells to produce useful quantities of the protein.