The Molecular Basis of Disease Variability among Cystic Fibrosis Patients Carrying the 3849+10 kb C→T Mutation

Chiba‐Falek, Ornit; Kerem, Eitan; Shoshani, Tzipora; Aviram, Micha; Augarten, A.; Bentur, Lea; Tal, Asher; Tullis, Elisabath; Rahat, Ayelet; Kerem, Batsheva

doi:10.1006/geno.1998.5517

Cited by 85 publications

(60 citation statements)

References 21 publications

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“…Nevertheless, we have also observed some severe clinical complications in class V patients probably attributable to the aging process; we should keep in mind that the c.2657 þ 5G4A CF patients analyzed in this study are in the upper range of the life expectancy among CF patients. It had been previously reported that splicing efficiency decreases with age, 27 thus it is not unexpected that the more advanced age of class V patients contributes to the low transcript levels observed and their subsequent severe lung disease. To provide some light on the genotype-phenotype relationship, it would be interesting to perform a replicate study, including younger CF patients, for instance, from neonatal screening programs.…”

Section: Discussionmentioning

confidence: 82%

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

et al. 2013

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The major purpose of the present study was to quantify correctly spliced CFTR transcripts in human nasal epithelial cells from cystic fibrosis (CF) patients carrying the splicing mutations c.580-1G4T (712-1G4T) and c.2657 þ 5G4A (2789 þ 5G4A) and to assess the applicability of this model in CFTR therapeutic approaches. We performed the relative quantification of CFTR mRNA by reverse transcription quantitative PCR (RT-qPCR) of these splicing mutations in four groups (wild type, CF-F508del controls, CF patients and CF carriers) of individuals. In addition, in vitro assays using minigene constructs were performed to evaluate the effect of a new CF complex allele c.[2657 þ 5G4A; 2562T4G]. Ex vivo qPCR data show that the primary consequence of both mutations at the RNA level is the skipping of their neighboring exon (6 and 16, respectively). The CFTR minigenes results mimicked the ex vivo data, as exon 16 skipping is the main aberrant transcript, and the correctly spliced transcript level was observed in a similar proportion when the c.2657 þ 5G4A mutation is present. In summary, we provide evidence 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.

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Section: Discussionmentioning

confidence: 82%

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

et al. 2013

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“…3849 + 10 kb C → T results in the creation of a partially active splice site in intron 19 that leads to the insertion of a new 84bp cryptic exon containing a premature inframe stop codon; thus both correctly spliced and aberrant transcripts can be produced simultaneously. When levels of aberrantly spliced CFTR transcripts were lower than 3% individuals showed no lung disease and normal lung function, whereas higher levels (9-28%) caused moderate or severe lung disease in these individuals (Chiba-Falek et al 1998). Variable levels of aberrantly spliced CFTR mRNA were found among patients with the same genotype, consistent with the variable nature of phenotypes caused by CFTR mutations, again suggestive of variation in the splicing factors rather than cis elements within the CFTR loci.…”

Section: Pancreatic Versus Pulmonary Diseasementioning

confidence: 72%

“…These results suggest that variability in splicing mechanisms of these CF individuals is associated with the variable penetrance of the disease. The splicing mutation 3849 + 10 kb C → T also exhibits correlation of CF pulmonary phenotype with the amount of normal CFTR transcripts (Chiba-Falek et al 1998). 3849 + 10 kb C → T results in the creation of a partially active splice site in intron 19 that leads to the insertion of a new 84bp cryptic exon containing a premature inframe stop codon; thus both correctly spliced and aberrant transcripts can be produced simultaneously.…”

Section: Pancreatic Versus Pulmonary Diseasementioning

confidence: 99%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

299

215

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SummaryCystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.

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“…It has been proposed that variations in the RNA splicing mechanism may lead to differential expression of the splicing mutation and hence to different amounts of aberrantly spliced mRNA (Chiba-Falek et al, 1998). Thus, Ars et al (2000) speculate that mutations affecting splicing could account for part of the clinical variability that is observed in NF1 patients carrying the same mutation.…”

Section: Discussionmentioning

confidence: 99%

Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients

et al. 2000

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Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting one in 3,500 individuals. The mutation rate in the NF1 gene is one of the highest known for human genes. Compared to other methods, the protein truncation test (PTT) provides improved efficiency in detecting NF1 mutations which are dispersed throughout the gene which spans 350 kilobases of genomic DNA. We have applied the PTT and subsequent sequence analysis of cloned cDNA to identify mutations in NF1 patients. We report here the identification of two novel (W336X and Q315X), and one recurrent (R304X) mutation located in exon 7 and show that all three premature termination codons lead to skipping of exon 7 in a proportion of the transcripts derived from the mutated allele. Possible mutation-induced alterations of the RNA secondary structure and their impact on skipping of exon 7 of the NF1 gene are explored and discussed.

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The Molecular Basis of Disease Variability among Cystic Fibrosis Patients Carrying the 3849+10 kb C→T Mutation

Cited by 85 publications

References 21 publications

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

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

The Phenotypic Consequences of CFTR Mutations

Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients

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