To investigate the impact of chloride (Cl–) permeability, mediated by residual activity of the cystic fibrosis transmembrane conductance regulator (CFTR) or by other Cl– channels, on the manifestations of cystic fibrosis (CF), we determined Cl– transport properties of the respiratory and intestinal tracts in ΔF508 homozygous twins and siblings. In the majority of patients, cAMP and/or Ca2+-regulated Cl– conductance was detected in the airways and intestine. Our finding of cAMP-mediated Cl– conductance suggests that, in vivo, at least some ΔF508 CFTR can reach the plasma membrane and affect Cl– permeability. In respiratory tissue, the expression of basal CFTR-mediated Cl– conductance, demonstrated by 30% of ΔF508 homozygotes, was identified as a positive predictor of milder CF disease. In intestinal tissue, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid–insensitive (DIDS-insensitive) Cl– secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive Cl– secretion was observed mainly in more severely affected patients. The more concordant Cl– secretory patterns within monozygous twins compared with dizygous pairs imply that genes other than CFTR significantly influence the manifestation of the basic defect.
Inez Bronsveld, Frauke Mekus, Jan Bijman, Manfred Ballmann, Hugo R. de Jonge, Ulrike Laabs, Dicky J. Halley, Helmut Ellemunter, Gianni Mastella, Stephen Thomas, Henk J. Veeze, Burkhard Tümmler