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

Ornit Chiba-Falek, Eitan Kerem, Tzipora Shoshani, Micha Aviram, Arei Augarten, Lea Bentur, Asher Tal, Elisabath Tullis, Ayelet Rahat, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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.

Original languageAmerican English
Pages (from-to)276-283
Number of pages8
Issue number3
StatePublished - 1 Nov 1998

Bibliographical note

Funding Information:
This work was supported by a grant from the Israeli Ministry of Health and from the North American CF Foundation to B.K.


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