Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings

To investigate the impact of chloride (Cl-) permeability mediated by residu al activity of the cystic fibrosis transmembrane conductance regulator (CFT R) or by other Cl- channels, on the manifestations of cystic fibrosis (CF), we determined Cl- transport properties of the respiratory and intestinal t racts in Delta F508 homozygous twins and siblings. In the majority of patie nts, 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 Delta F508 CFTR can reach the plasma membrane and a ffect Cl- permeability. In respiratory tissue, the expression of basal CFTR -mediated Cl- conductance, demonstrated by 30% of Delta F508 homozygotes, w as identified as a positive predictor of milder CF disease. In intestinal t issue, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive (DIDS -insensitive) Cl- secretion, which is indicative of functional CFTR channel s, correlated with a milder phenotype, whereas DIDS-sensitive Cl- secretion was observed mainly in more severely affected patients. The more concordan t Cl- secretory patterns within monozygous twins compared with dizygous pai rs imply that genes other than CFTR significantly influence the manifestati on of the basic defect.