Cystic Fibrosis Transmembrane Conductance Regulator Intracellular Processing, Trafficking, and Opportunities for Mutation-Specific Treatment

Rogan, Mark P.; Stoltz, David A.; Hornick, Douglas B.

doi:10.1378/chest.10-2077

Cited by 130 publications

(146 citation statements)

References 104 publications

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“…The CFTR gene is located on the long arm of chromosome 7 at position q31.2 [9]. To date, over 1,900 sequence variations in the CFTR gene have been reported [10], although a detailed understanding of how CFTR mutations impact channel dysfunction is limited to a only a few of these [11].…”

Section: Genetics Of Cftrmentioning

confidence: 99%

“…This implies a relatively small list of welldefined CFTR mutations known to be CF disease causing, whereas the functional consequence of various rare sequence variations remains unknown or has been shown not to be CF disease causing [12]. The majority of identified CFTR gene mutations fall into one of six classes that account for ,80% of all CF patients [9]. Of the .1,900 CFTR mutations that have been identified so far, approximately only 20 mutations have a frequency .0.1% [9].…”

Section: Genetics Of Cftrmentioning

confidence: 99%

“…The majority of identified CFTR gene mutations fall into one of six classes that account for ,80% of all CF patients [9]. Of the .1,900 CFTR mutations that have been identified so far, approximately only 20 mutations have a frequency .0.1% [9]. In fact, notwithstanding the common F508del variant, only four CFTR mutations have a frequency .0.1%: G551D, W1282X, G542X and N1303K, having a worldwide prevalence of around 1-3% each [9,11].…”

Section: Genetics Of Cftrmentioning

confidence: 99%

“…Of the .1,900 CFTR mutations that have been identified so far, approximately only 20 mutations have a frequency .0.1% [9]. In fact, notwithstanding the common F508del variant, only four CFTR mutations have a frequency .0.1%: G551D, W1282X, G542X and N1303K, having a worldwide prevalence of around 1-3% each [9,11]. F508del is the most common mutation with an allelic frequency of around 90% worldwide [13].…”

Section: Genetics Of Cftrmentioning

confidence: 99%

“…Class II mutations, including F508del, have folding or maturation defects, which can result in premature CFTR degradation ( fig. 1) [9].…”

Section: Mutation Classificationmentioning

confidence: 99%

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Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

102

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Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

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Section: Genetics Of Cftrmentioning

confidence: 99%

Section: Genetics Of Cftrmentioning

confidence: 99%

Section: Genetics Of Cftrmentioning

confidence: 99%

Section: Genetics Of Cftrmentioning

confidence: 99%

“…Class II mutations, including F508del, have folding or maturation defects, which can result in premature CFTR degradation ( fig. 1) [9].…”

Section: Mutation Classificationmentioning

confidence: 99%

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Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

102

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Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

Sinha

Southern

Dwan

et al. 2014

Cochrane Database of Systematic Reviews

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Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

Southern

Patel

Sinha

et al. 2018

Cochrane Database of Systematic Reviews

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There is insufficient evidence that monotherapy with correctors has clinically important effects in people with CF who have two copies of the F508del mutation.Combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) each result in similarly small improvements in clinical outcomes in people with CF; specifically improvements quality of life (moderate-quality evidence), in respiratory function (high-quality evidence) and lower pulmonary exacerbation rates (moderate-quality evidence). Lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (high-quality evidence). These adverse effects were not observed for tezacaftor-ivacaftor. Tezacaftor-ivacaftor has a better safety profile, although data are not available for children younger than 12 years. In this age group, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the increase in blood pressure and shortness of breath seen in longer-term data in adults when considering this combination for use in young people with CF.

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Cystic Fibrosis Transmembrane Conductance Regulator Intracellular Processing, Trafficking, and Opportunities for Mutation-Specific Treatment

Cited by 130 publications

References 104 publications

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

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