Cystic Fibrosis: An overview.

Cystic Fibrosis (CF) was regarded as an invariably lethal autosomal recessive disorder carried by a mutated gene (CFTR) on chromosome seven. Two faulty copies of the gene responsible for CF produce a phenotype (expression pattern) associated with malabsorption and maldigestion of food and nutrients from the intestine due to a failure of fluid secretions by the intestinal crypt epithelium and pancreatic ducts (enzymes), causing intestinal blockage (meconium ileus), previously the primary cause of death in CF children. In addition the gene responsible causes a failure of secretion of salt (NaCl) and water from the airways of the lung resulting in an inability to clear mucus and bacteria from the lung and the creation of additional binding sites for bacteria that progressively destroy the airway tissue. The consequence is a dry, infected 'cystic fibrotic' lung. Other affected tissues include the sweat gland, where the sweat duct cannot reabsorb NaCl and hence dilute the sweat; the liver; and the ovaries, uterus and vas deferens of the testes, which leads to infertility in both affected males and females.

The frequency of the CF allele may be as high as 5% of the caucasian population, leading to a CF incidence in the region of 1 in 2000 of all caucasian births, an extraordinarily high prevalence for such a lethal mutation. The discrepancy between the prevalence of the CF gene in the population (1 in 20 are carriers) and the incidence of the disease may be explained by the high reported infertilty amongst male carriers of the affected gene.  Their vas deferens of the male heterozygote is frequently obstructed, preventing the passage of spermatozoa.  The explanation as to why CF is the world's commonest lethal heritable condition rests in the advantage of carrying just one copy of the CF gene. Just as the sickle cell anaemia heterozygote (one faulty gene) protects against the malarial parasite, so the CF heterozygote protects against the entry of the typhoid bacterium across the intestinal epithelial lining, and were therefore presumably favoured during the great European typhoid epidemics. The most frequent CF mutation (around 70% of CF mutations are 'delta' F508 mutations which cause the deletion of a single phenylalanine amino acid residue from position 508 of the CF protein) results in the failure of the efficient transfer of the CF gene product to the apical membrane of the epithelial cells lining the airways and the crypt regions of the small and large intestines.

The CF gene, cloned by Francis Collins and co-workers in 1989, was surprisingly found to encode a membrane-spanning chloride channel which is opened upon phosphorylation of the protein's R domain by cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG, in the intestine) and/or calcium-dependent protein kinase, PKC. CF mutations thus block NaCl secretion in response to cyclic AMP-mobilising hormones (and bacteria causing fluid hypersecretion, or diarrhoea) such as vasoactive intestinal polypeptide (and cholera toxin) leading to a failure of the hydration of the intestine and airways (and an advantageous protection against secretory diarrhoea). A detailed study of the cell biology of the epithelia implicated in CF has led to potential pharmaceutical and gene therapeutic strategies for CF.   Attention has in recent years focused upon treatments for the complications to the airways, and fresh emphasis upon the reproductive and intestinal complications of the disorder needs now to be addressed.

Primary epithelia affected in Cystic Fibrosis

Top CF Main Page Front Page