Two Patients with Cystic Fibrosis, Nonsense Mutations in Each Cystic Fibrosis Gene, and Mild Pulmonary Disease

Abstract

CYSTIC fibrosis is the most common lethal inherited disorder in the white population. It is manifested by viscous secretions in the lungs and pancreas and abnormal electrolyte composition of sweat.¹ Epithelial cells from patients with cystic fibrosis have abnormal conductance of chloride ions across apical membranes due to defective regulation of a particular chloride channel.^{2 3 4} Inadequate secretion of chloride is believed to cause the insufficient hydration of mucus in the airways and pancreatic ducts.¹ The cystic fibrosis gene has recently been identified, and it is predicted to encode a 1480-amino-acid protein termed the cystic fibrosis transmembrane conductance regulator (CFTR).^{5 , 6} The deduced amino acid sequence of CFTR suggests that this protein has several functionally important regions, including two ATP-binding domains, two areas that interact with cell membranes, and a highly charged domain with several potential sites for phosphorylation by protein kinases. The structure of CFTR is similar to the multidrug-resistance proteins and several other membrane-associated ATP-binding proteins.⁶ The latter proteins are known to transport small molecules (drugs, carbohydrates, and amino acids) across cell membranes in a process that appears to be coupled with ATP hydrolysis.^{7 , 8} Structural similarities between CFTR and this family of proteins raise the possibility that CFTR may be involved in the regulation of secretory chloride channels.^{6 , 9}