TY - JOUR
T1 - 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
AU - Mickle, John E.
AU - Milewski, Michał J.
AU - Macek, Milan
AU - Cutting, Garry R.
N1 - Funding Information:
The authors thank Drs. Tom Hargrove, Antony Shrimpton, and Thilo Doerk for clinical and mutation data. We are grateful to Dr. Bill Guggino for critical review of the manuscript. This work was supported in part by IGA MZ CR grants 2899-5 and 3526-3 (to M.M.) and by National Institutes of Health grant DK44003 and Specialized Center for Organized Research grant DK48977 (to G.R.C.).
PY - 2000
Y1 - 2000
N2 - The protein defective in cystic fibrosis (CF), the CF transmembrane- conductance 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 regulatory function. To address this issue, we transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral 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), ΔF508, functioned as a chloride channel but did not regulate ORCCs. However, CFTR bearing disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels.
AB - The protein defective in cystic fibrosis (CF), the CF transmembrane- conductance 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 regulatory function. To address this issue, we transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral 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), ΔF508, functioned as a chloride channel but did not regulate ORCCs. However, CFTR bearing disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels.
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U2 - 10.1086/302893
DO - 10.1086/302893
M3 - Article
C2 - 10762539
AN - SCOPUS:0033926811
SN - 0002-9297
VL - 66
SP - 1485
EP - 1495
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -