Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis.

  title={Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis.},
  author={Anabela Santo Ramalho and Sebastian Beck and Michelle E Meyer and Deborah Penque and Garry R. Cutting and Margarida D. Amaral},
  journal={American journal of respiratory cell and molecular biology},
  volume={27 5},
  • A. RamalhoS. Beck M. Amaral
  • Published 1 November 2002
  • Biology, Medicine
  • American journal of respiratory cell and molecular biology
Estimates of the level of transcripts from the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene required to develop a CF phenotype range from 4-20% of normal. Due to the importance of obtaining reliable data on this issue for therapeutic strategies, we developed a novel polymerase chain reaction-based method to quantify CFTR transcripts and applied it to the analysis of nasal epithelium RNA of five patients with CF and the 3272-26A>G/F508del genotype. We calculated that 8.2… 

Figures and Tables from this paper

Assessing the residual CFTR gene expression in human nasal epithelium cells bearing CFTR splicing mutations causing cystic fibrosis

Evidence is provided that ex vivo quantitative transcripts analysis using RT/qPCR is a robust technology that could be useful for measuring the efficacy of therapeutic approaches that attempt to achieve an increase in CFTR gene expression.

Pharmacological Rescue of Mutant CFTR Function for the Treatment of Cystic Fibrosis

In vivo analysis ofCFTR activity in CF patients indicates that it is correlated with the severity of lung disease and supports the hypothesis that CFTR modulators that restore mutant CFTR activity to >10% of wild-type-CFTR would improve lung function.

CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.

Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.

Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides

Cystic fibrosis (CF), the most common life‐threatening genetic disease in Caucasians, is caused by ∼2,000 different mutations in the CF transmembrane conductance regulator (CFTR) gene. A significant

Functional stability of rescued delta F508 cystic fibrosis transmembrane conductance regulator in airway epithelial cells.

The results strongly support the idea that maximal correction of Delta F508 CFTR requires a chemical corrector that promotes folding and exit from the endoplasmic reticulum; enhances surface stability; and improves channel activity.

Unravelling the Regions of Mutant F508del-CFTR More Susceptible to the Action of Four Cystic Fibrosis Correctors

Three out of four correctors seem to specifically improve the expression and the maturation of the mutant CFTR N-half (M1N1, residues 1–633) and the CFTR C- half (M2N2, residues 837–1480), which appears to be the region mainly affected by corr4a.

Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators.

Results indicate that most individuals with CF carrying missense variants are likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and likely to derive the greatest benefit from combination therapy.

The holy grail of cystic fibrosis research: pharmacological repair of the F508del-CFTR mutation.

Therapeutic strategies aimed at correcting the defect of the cystic fibrosis transmembrane conductance regulator (CFTR) (“CFTR-repair”) constitute a new avenue towards the treatment of patients

CFTR and Cystic Fibrosis: From Structure to Function

The basic aspects of Cystic Fibrosis as a disorder are covered, focusing on its genetics and mutation prevalence/incidence, and the major part is devoted to the CFTR protein—its structure and classification within the ABC transporter superfamily, its biogenesis with membrane insertion and chaperone-assisted folding, its glycosylation and the endoplasmic reticulum quality control mechanisms that assess CFTR folding status.

What’s new in cystic fibrosis? From treating symptoms to correction of the basic defect

Recent therapeutic strategies that either target the underlying defect or the early steps in CF pathophysiology are highlighted, including PTC124, a new chemical compound that selectively induces read-through of premature stop codons.



The molecular basis of partial penetrance of splicing mutations in cystic fibrosis.

There is variability in the efficiency of the splicing mechanism, among different individuals and between different organs of the same individual, which provides the molecular basis of the partial penetrance of cystic fibrosis disease in patients carrying the 5T allele.

A delta F508 mutation in mouse cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo.

The data show that like its human homologue, mouse delta F508-CFTR is a temperature sensitive processing mutant, which may help to elucidate the processing pathways of complex membrane proteins and facilitate the discovery of new approaches towards therapy of cystic fibrosis.

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

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 is identified, indicating that this syndrome is a form of cystic Fibrosis.

A 32‐bp deletion (2991del32) in the cystic fibrosis gene associated with CFTR mRNA reduction

The identification of a 32‐bp deletion within the coding region of CFTR that involves the nucleotides 2991–3022 in exon 15 (2991del32) is described, which indicates that the 32‐BP deletion causes a pancreas insufficient cystic fibrosis phenotype by a severe reduction ofCFTR mRNA.

Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens.

The 5-thymidine (5T) variant of the cystic fibrosis transmembrane conductance regulator (CFTR) intron 8 polypyrimidine tract (IVS8-T tract) is the most frequent CFTR gene alteration identified in men

Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study

The relationship between genotype, that is, the mutations in the CFTR gene, and the clinical phenotype of CF patients has been difficult to establish, in particular for lung disease.

Identification of a splice site mutation (2789+5 G>A) associated with small amounts of normal CFTRmRNA and mild cystic fibrosis

It is proposed that this small amount of normally spliced mRNA is associated with synthesis of some normal CFTR protein, and accounts for the mild phenotype of CF patients bearing this form of mutation.

Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA

An inverse relationship between the length of the polythymidine tract at the exon 9 splice branch/acceptor site and the proportion of exon9− CFTR mRNA transcripts is found and strongly indicates a genetic basis in vivo modulating post–transcriptional processing of CFTR transcripts.

Complex cystic fibrosis allele R334W‐R1158X results in reduced levels of correctly processed mRNA in a pancreatic sufficient patient

A three‐generation CF family with a complex CFTR allele that has not been previously described, containing the missense mutation R334W in exon 7 and the nonsense mutation R1158X inExon 19 is described.