Chloride conductance and genetic background modulate the cystic fibrosis phenotype of ΔF508 homozygous twins and siblings

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 AF508 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.

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