The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation.

Journal Article (Journal Article)

Disease severity varies among cystic fibrosis (CF) patients carrying the same CFTR genotype. Here we studied the mechanism underlying disease variability in individuals carrying a splicing CFTR mutation, 3849+10 kb C-->T. This mutation was shown to produce both correctly and aberrantly spliced CFTR transcripts containing an additional cryptic exon. Semiquantitative nondifferential RT-PCR showed considerable variability in the level (0-28%) of aberrantly spliced RNA transcribed from the 3849+10 kb C-->T mutation in nasal epithelium from 10 patients. A significant inverse correlation was found between the level of the aberrantly spliced CFTR transcripts and pulmonary function, expressed as FEV1 (r = 0.92, P < 0.0001). Patients with normal pulmonary function (FEV1 > 80% predicted) had lower levels of aberrantly spliced CFTR RNA (0 to 3%) than those with FEV1 < 80%, (9 to 28% aberrantly spliced RNA). Only aberrantly spliced CFTR RNA was detected in the lung of a patient with severe lung disease who underwent lung transplantation. Our results show that the severity of CF lung disease correlates with insufficiency of normal CFTR RNA. Thus, the regulation of alternative splice site selection may be an important mechanism underlying partial penetrance in CF. Further understanding of this regulation will contribute to potential therapy for patients carrying splicing mutations in human disease genes.

Full Text

Duke Authors

Cited Authors

  • Chiba-Falek, O; Kerem, E; Shoshani, T; Aviram, M; Augarten, A; Bentur, L; Tal, A; Tullis, E; Rahat, A; Kerem, B

Published Date

  • November 1, 1998

Published In

Volume / Issue

  • 53 / 3

Start / End Page

  • 276 - 283

PubMed ID

  • 9799593

International Standard Serial Number (ISSN)

  • 0888-7543

Digital Object Identifier (DOI)

  • 10.1006/geno.1998.5517


  • eng

Conference Location

  • United States