Cystic Fibrosis mutations characterised.

More than 1,900 errors in the gene responsible for cystic fibrosis (CF) have been discovered through gene sequencing techniques but it is unclear how many of them actually cause problems that contribute to this inherited disease. 

Now a team of researchers from the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine have conducted a large study to try to determine which mutations are benign and which are causes of the disease. In order for the disease to be expressed a person has to have a deleterious mutation in both copies of the gene. These may be the same or different mutations in each copy of the gene. If a person has a mutation in only one of their two copies of the gene they are said to be a carrier of the disease but are not affected themselves. However if two parents are both carriers of harmful mutations then one in four of their children will be affected by the disease.

“Since not all mutations cause disease, sequencing the DNA in both copies of your CFTR gene and finding an abnormality in one wouldn’t tell us if you are a carrier for CF unless we knew if that abnormality causes CF,” says Garry Cutting, M.D., professor of paediatrics in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. “Until this new work, more than a quarter of couples in which both partners were found to carry a CFTR mutation were left wondering if their mutations were going to affect their offspring. Now it’s down to 9 percent,” he says.

The team began its study with a database containing the genetic information of nearly 40,000 patients with CF. It then examined the 159 mutations that occurred in the database at a frequency of at least 0.01 percent. (Most of the more than 1,900 known mutations are even rarer than that.) The research team analysed each of these mutations to determine its clinical relevance and its effect on the work of the CFTR protein. The impact of each mutation on patients’ health was assessed by first examining data on the salt concentrations in the sweat of patients bearing each particular mutation. CF causes unusually high amounts of salt to appear in sweat, so a mutation was deemed clinically significant if patients carrying that mutation had high reported salt concentrations.

The team then looked at how each genetic error affected the protein made by the CFTR gene. Eighty of the mutations would prevent the production of any CFTR protein based on the location of the mutation. These were classified as disease-causing, Cutting said. The remaining 77 mutations were tested biochemically in cells to determine the amount of damage sustained by the CFTR protein in each case.

In total, 127 of the 159 mutations were shown to cause CF, if inherited with another CF-causing mutation. Of those, 105 had never before been characterized. This study has increased the number of known CF-causing mutations from 22 to 127, accounting for 95 percent of the variations found in patients with CF.

This work will not only give certainty to many prospective parents who carry mutations that had not been characterised previously, it will also help research groups that are trying to develop drugs that correct the malfunction caused by particular mutations. The results of the study are already being used by CF clinicians to aid in diagnosis, by public health experts to refine newborn screening and by researchers investigating new therapeutics. The team is also continuing to analyse the rest of the mutations in the database — those with a frequency of less than 0.01 percent — and has already found 49 more that are CF-causing. Updates can be found at the project’s website ( “We don’t want to stop where we are and forget about the patients with the rarest mutations. We will leave no one behind,” says Professor Cutting.

Sources and further reading
Johns Hopkins Medicine press release
Nature Genetics article abstract

Related Pages
On this site

Tests: Sweat Test
Condition: Cystic Fibrosis
Inside the lab: Clinical Genetic Testing

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