A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations

N Engl J Med. 1994 Oct 13;331(15):974-80. doi: 10.1056/NEJM199410133311503.


Background: Many patients with chronic pulmonary disease similar to that seen in cystic fibrosis have normal (or nondiagnostic) sweat chloride values. It has been difficult to make the diagnosis of cystic fibrosis in these patients because no associated mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been identified.

Methods: We evaluated 23 patients with pulmonary disease characteristic of cystic fibrosis but with sweat chloride concentrations in the normal range. Mutations in the CFTR gene were sought by direct sequencing of polymerase chain reaction-amplified nasal epithelial messenger RNA and by testing the functioning of affected epithelium.

Results: A cytidine phosphate guanosine dinucleotide C-to-T point mutation in intron 19 of the CFTR gene, termed 3849 + 10 kb C to T, was identified in 13 patients from eight unrelated families. This mutation was found in patients from three different ethnic groups with three different extended haplotypes. The mutation leads to the creation of a partially active splice site in intron 19 and to the insertion into most CFTR transcripts of a new 84-base-pair "exon," containing an in-frame stop codon, between exons 19 and 20. Normally spliced transcripts were also detected at a level approximately 8 percent of that found in normal subjects. This mutation is associated with abnormal nasal epithelial and sweat acinar epithelial function.

Conclusions: We have identified a point mutation in intron 19 of CFTR and abnormal epithelial function in patients who have cystic fibrosis-like lung disease but normal sweat chloride values. The identification of this mutation indicates that this syndrome is a form of cystic fibrosis. Screening for the mutation should prove diagnostically useful in this population of patients.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Base Sequence
  • Child
  • Child, Preschool
  • Chloride Channels / metabolism
  • Chlorides / analysis*
  • Chromosomes, Human, Pair 17
  • Cystic Fibrosis / diagnosis*
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Female
  • Humans
  • Introns
  • Lung Diseases, Obstructive / diagnosis*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Mutation
  • Nasal Mucosa / metabolism
  • Polymerase Chain Reaction
  • RNA, Messenger / metabolism
  • Sweat / chemistry*


  • CFTR protein, human
  • Chloride Channels
  • Chlorides
  • Membrane Proteins
  • RNA, Messenger
  • Cystic Fibrosis Transmembrane Conductance Regulator