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

@article{Ramalho2002FivePO,
  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},
  year={2002},
  volume={27 5},
  pages={
          619-27
        }
}
  • 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… 

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References

SHOWING 1-10 OF 47 REFERENCES

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.