Expression and characterization of the cystic fibrosis transmembrane conductance regulator

Article Abstract:

Cystic fibrosis (CF) is the most common deadly inheritable disease among Caucasians. CF is characterized by defective salt transport in organs, particularly the lungs, sweat glands, intestines, and pancreas. The major cellular defect in CF patients involves the function and regulation of chloride channels. These channels, which are proteins embedded in the membranes of epithelial cells (which form the exterior layers of most body surfaces), allow the movement of chloride ions from the cell interior to the exterior. In normal epithelial cells, the chloride channel opens when it is phosphorylated (modified by the addition of phosphate) by a kinase (a type of enzyme). In CF cells, chloride channels are present but they cannot be activated by the kinase, and thus cannot secrete chloride ions or fluid. A major research finding in 1989 was the isolation of a gene which had a mutation in 70 percent of patients with CF. The gene codes for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), but the actual function of the protein has not yet been determined. This article describes work done with the gene to allow synthesis of the protein from the gene information by means of laboratory techniques. The results show that the protein is a membrane-associated protein to which sugar molecules attach during synthesis, which is common for membrane-bound proteins. In addition, this synthesized, or recombinant, CFTR can be phosphorylated by the kinase, which regulates chloride channels (as well as other proteins). Antibodies that recognize the native protein also recognize recombinant CFTR. These results indicate that recombinant CFTR is structurally and functionally equivalent to CFTR, and this will allow CFTR function to be studied with the aim of improving diagnosis and therapy of cystic fibrosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Analysis, Recombinant DNA, Proteins

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Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells

Article Abstract:

Cystic fibrosis (CF) is the most common deadly inheritable disease affecting Caucasians. CF is characterized by defective salt transport in organs, particularly the lungs, sweat glands, intestines, and pancreas. The major cellular defect in CF patients involves the function and regulation of chloride channels. These channels, which are proteins embedded in the membranes of epithelial cells (which form the exterior layers of most body surfaces), allow the movement of chloride ions from the cell interior to the exterior. In normal epithelial cells, the chloride channel opens when it is phosphorylated (modified by the addition of phosphate) by a kinase (a type of enzyme). In CF cells, chloride channels are present but they cannot be activated by the kinase, and thus cannot secrete chloride ions or fluid. A major research finding in 1989 was the isolation of a gene which contained a mutation in 70 percent of patients with CF. The gene codes for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and work is ongoing to determine the actual function of this protein. The results described in this article show that when CFTR is added to CF cells, which have the mutated CFTR and are thereby defective in chloride transport, the defect in chloride secretion is corrected. This demonstrates a causal relationship between CFTR mutations and the actual dysfunctions associated with CF. The results also suggest that CFTR is either a chloride channel or that it regulates chloride channels, but it cannot be determined which of these two possibilities is true. The study suggests that treatment of CF by correcting the underlying defect may some day be feasible. (Consumer Summary produced by Reliance Medical Information, Inc.)

Genetic aspects, Chloride channels

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Mutation in CFTR associated with mild-disease-form Cl- channels with altered pore properties

Article Abstract:

Missense mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) are associated with milder cystic fibrosis. Replacements of arginine with histidine at residue 117, tryptophan at residue 334 or proline at residue 347 affect basic amino acids located at the external end of the second and the sixth putative membrane-spanning sequences. It is reported that all three mutants are correctly processed and generate cyclic AMP-regulated Cl- currents when expressed in heterologous epithelial cells.

Ion channels, Mutagenesis

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