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Previous Volume 331:974-980 October 13, 1994 Number 15 Next

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ABSTRACT

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.

Source Information

From the Applied Technology Genetics Corp., Malvern, Pa. (W.E.H.); the Department of Medicine (L.H.B., Z.Z., J.C.O., R.C.B., M.R.K.) and the Division of Molecular Pathology (Z.Z., K.J.F., L.M.S.), University of North Carolina, Chapel Hill; Children's Hospital Medical Center, Cincinnati (T.E.B.); the Department of Pediatrics, Duke University, Durham, N.C. (A.S.); Schneider Children's Hospital-Long Island Jewish Medical Center, New Hyde Park, N.Y. (J.D.G.); and the Pediatric Pulmonary Division, Columbia-Presbyterian Medical Center, New York (L.Q.).

Address reprint requests to Dr. Knowles at the Division of Pulmonary Diseases, 724 Burnett-Womack Bldg., CB 7020, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7020.

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