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

Nature. 1993 Mar 11;362(6416):160-4. doi: 10.1038/362160a0.


The cystic fibrosis transmembrane conductance regulator (CFTR) is a phosphorylation-regulated Cl- channel located in the apical membrane of epithelia. Although cystic fibrosis (CF) is caused by mutations in a single gene encoding CFTR, the disease has a variable clinical phenotype. The most common mutation associated with cystic fibrosis, deletion of a phenylalanine at position 508 (frequency, 67%), is associated with severe disease. But some missense mutations, for example ones in which arginine is replaced by histidine at residue at 117 (R117H; 0.8%), tryptophan at 334 (0.4%), or proline at 347 (0.5%), are associated with milder disease. These missense mutations affect basic residues located at the external end of the second (M2) and in the sixth (M6) putative membrane-spanning sequences. Here we report that, when expressed in heterologous epithelial cells, all three mutants were correctly processed and generated cyclic AMP-regulated apical Cl- currents. Although the macroscopic current properties were normal, the amount of current was reduced. Patch-clamp analysis revealed that all three mutants had reduced single-channel conductances. In addition, R117H showed altered sensitivity to external pH and had altered single-channel kinetics. These results explain the quantitative decrease in macroscopic Cl- current, and suggest that R117, R334 and R347 contribute to the pore of the CFTR Cl- channel. Our results also suggest why R117H, R334W and R347P produce less severe clinical disease and have implications for our understanding of cystic fibrosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Chloride Channels
  • Cyclic AMP / physiology
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / physiopathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Epithelium / physiology
  • HeLa Cells
  • Humans
  • Ion Channels / genetics
  • Ion Channels / physiology*
  • Membrane Potentials
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mutation*
  • Rats
  • Rats, Inbred F344
  • Thyroid Gland / physiology
  • Transfection


  • CFTR protein, human
  • Chloride Channels
  • Ion Channels
  • Membrane Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cyclic AMP