title: The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation.
abstract: 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.
authors.affiliation: Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Chiba-Falek
authors.forename: E
authors.initials: E
authors.lastname: Kerem
authors.forename: T
authors.initials: T
authors.lastname: Shoshani
authors.forename: M
authors.initials: M
authors.lastname: Aviram
authors.forename: A
authors.initials: A
authors.lastname: Augarten
authors.forename: L
authors.initials: L
authors.lastname: Bentur
authors.forename: A
authors.initials: A
authors.lastname: Tal
authors.forename: E
authors.initials: E
authors.lastname: Tullis
authors.forename: A
authors.initials: A
authors.lastname: Rahat
authors.forename: B
authors.initials: B
authors.lastname: Kerem
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D002648:Child; D003550:Cystic Fibrosis / Q000235:genetics* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012313:RNA