Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes

Cystic fibrosis is a heterogenic disease, in which the phenotype can also vary for patients with the same genotype. In the present study the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in nasal epithelial cells from 19 adult patients with cystic fibrosis was investigated. All patients had severe mutations, whereby no or little functional CFTR is expected in the plasma membrane. Of the patients, 15 were homozygous for DeltaF508-CFTR (i.e. CTFR lacking residue Phe-508). The others were DeltaF508-heterozygous with 3659delC, 394delTT or 2183AA-->G. Nasal epithelial cells, obtained by nasal brushings, were loaded with the fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide to measure Cl- efflux. In most of the cystic fibrosis patients, forskolin plus isobutylmethylxanthine was unable to elicit any response. Unexpectedly, cells from three cystic fibrosis patients (two DeltaF508/DeltaF508 patients and one DeltaF508/3659delC patient) responded to stimulation in a wild-type manner. It was investigated whether this residual chloride transport function was associated with a milder phenotype. Clinical parameters studied were lung function, number of antibiotic courses, Shwachman score, Bhalla score, age at chronic colonization with Pseudomonas aeruginosa and the pattern of essential fatty acids in serum phospholipids. Unknown factors may affect the presence of functional CFTR in patients with severe CFTR mutations. However, we could not find a correlation between the response to cAMP and any of the phenotype parameters. It appears that functional cAMP transport in the nasal epithelium is no guarantee of a mild phenotype and, conversely, that a patient lacking cAMP-dependent chloride transport can develop a mild phenotype.