Cystic fibrosis

What it is

Cystic fibrosis is an autosomal recessive disorder causing increased viscosity of secretions, for example in the lungs and pancreas. It is one of the most common monogenic recessively inherited diseases, especially in Caucasians, and is named the most common lethal genetic disease in the Caucasian population. The defect lies in the CFTR gene, the cystic fibrosis transmembrane conductance regulator, on the long arm of chromosome 7, and the mutation is most commonly a phenylalanine deletion, Phe508.

CFTR encodes an ATP-gated chloride channel that secretes chloride in the lungs and GI tract and reabsorbs chloride in the sweat glands. In the most common mutation the protein is misfolded and retained in the RER and not transported to the cell membrane, so chloride and water secretion fall; the rise in intracellular chloride results in compensatory sodium reabsorption through the epithelial sodium channels and with it water reabsorption, so the mucus secreted into the lungs and GI tract is abnormally thick. The increased sodium reabsorption also makes the transepithelial potential difference more negative. Put shortly, this is a chloride channel defect in the exocrine glands: impaired chloride secretion, massive sodium absorption and water movement through the epithelium, so the surface is dehydrated.

Which gene is the question with a local answer: worldwide the most commonly implicated gene is Delta F508, but in Oman it is S549R. The disease is caused by over 2000 different mutations in the CFTR gene. In Oman genetic testing for cystic fibrosis was initiated in 1995 by sending samples abroad to be tested for a panel of mutations found commonly in Caucasians, and most of those results were negative for the tested mutations, while the in house lab data indicated that over 60% of the tested samples were positive. CFTR mutations are grouped into classes, and the prevalence of the different mutational classes in the population, with the most common mutations in each group, is what directs class-specific correction or modulation of the underlying CFTR defect.

Asked for the genetic basis, the answer is that cystic fibrosis is autosomal recessive and the gene sits on chromosome 7, that the affected protein is the one for the cAMP-regulated chloride channels, and that the commonest gene is the F508 deletion.