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Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency.
- Source :
-
The EMBO journal [EMBO J] 1995 Mar 01; Vol. 14 (5), pp. 876-83. - Publication Year :
- 1995
-
Abstract
- Variability in the severity of cystic fibrosis (CF) is in part due to specific mutations in the CF transmembrane conductance regulator (CFTR) gene. To understand better how mutations in CFTR disrupt Cl- channel function and to learn about the relationship between genotype and phenotype, we studied two CF mutants, A455E and P574H, that are associated with pancreatic sufficiency. A455E and P574H are located close to conserved ATP binding motifs in CFTR. Both mutants generated cAMP-stimulated apical membrane Cl- currents in heterologous epithelial cells, but current magnitudes were reduced compared with wild-type. Patch-clamp analysis revealed that both mutants had normal conductive properties and regulation by phosphorylation and nucleotides. These mutants had normal or increased Cl- channel activity: A455E had an open-state probability (Po) similar to wild-type, and P574H had an increased Po because bursts of activity were prolonged. However, both mutants produced less mature glycosylated protein, although levels were greater than observed with the delta F508 mutant. These changes in channel activity and processing provide a quantitative explanation for the reduced apical Cl- current. These data also dissociate structural requirements for channel function from features that determine processing. Finally, the results suggest that the residual function associated with these two mutants is sufficient to confer a milder clinical phenotype and infer approaches to developing treatments.
- Subjects :
- Animals
Cyclic AMP agonists
Cystic Fibrosis genetics
Cystic Fibrosis Transmembrane Conductance Regulator
Epithelial Cells
Epithelium metabolism
HeLa Cells
Humans
Ion Channel Gating
Membrane Proteins metabolism
Pancreas metabolism
Patch-Clamp Techniques
Phosphorylation
Rats
Rats, Inbred F344
Thyroid Gland physiology
Adenosine Triphosphate metabolism
Chloride Channels metabolism
Membrane Proteins genetics
Mutation physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0261-4189
- Volume :
- 14
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 7534226
- Full Text :
- https://doi.org/10.1002/j.1460-2075.1995.tb07069.x