Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels

The protein defective in cystic fibrosis (CF), the CF transmembrane-conduct ance regulator (CFTR), functions as an epithelial chloride channel and as a regulator of separate ion channels. Although the consequences that disease -causing mutations have on the chloride-channel function have been studied extensively, little is known about the effects that mutations have on the r egulatory function. To address this issue, we transiently expressed CFTR-be aring mutations associated with CF or its milder phenotype, congenital bila teral absence of the vas deferens, and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF -associated mutation in the first nucleotide-binding domain (NBD1), Delta F 508, functioned as a chloride channel but did not regulate ORCCs. However, CFTR bearing disease-associated mutations in other domains retained both fu nctions, regardless of the associated phenotype. Thus, a relationship betwe en Loss of CFTR regulatory function and disease severity is evident for NBD 1, a region of CFTR that appears important for regulation of separate chann els.