Washington: A group of researchers have made a significant breakthrough for figuring out which mutations are benign and which are deleterious in cystic fibrosis.
Researchers have now raised the number of known CF-causing mutations from 22 to 127, accounting for 95 percent of the variations found in patients with CF.
The scientists said that characterizing those additional mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene will not only bring certainty to families about a CF diagnosis or carrier status, but will also accelerate the design process for new drugs tailored to a particular mutation.
Garry Cutting, M.D., professor of pediatrics in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine, said that 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.
He said that 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.
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 more rare than that.) The research team analyzed 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.
The study has been published online in Nature Genetics.
ANI
