The Phenotypic Consequences of <i>CFTR</i> Mutations

Rowntree, Rebecca K.; Harris, Ann

doi:10.1046/j.1469-1809.2003.00028.x

Cited by 299 publications

(226 citation statements)

References 78 publications

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“…1). Class I mutations can result from nonsense and frame-shift mutations, as well as mRNA splicing defects [14]. For example, G542X is a nonsense or stop mutation, where introduction of a premature termination codon (or stop codon) results in premature cessation of translation and production of truncated CFTR protein.…”

Section: Mutation Classificationmentioning

confidence: 99%

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: Mutation Classificationmentioning

confidence: 99%

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

Derichs

2013

European Respiratory Review

102

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“…The grouping of mutations into functional categories is as follows: class I, no synthesis of CFTR; class II, degradation of CFTR in the endoplasmic reticulum; class III, transport of CFTR to the cell membrane, but no appropriate response; class IV, diminished action of CFTR in the cell membrane; and class V, normal but inadequate amounts of CFTR (12). Many studies document associations between functional class and complications of cystic fibrosis, including pancreatic dysfunction (13,15).…”

Section: Risk Factorsmentioning

confidence: 99%

“…Genotypes associated with cystic fibrosis were coded into five established classes reflecting CFTR function of defective production, processing, regulation, conductance, and quantity of CFTR protein (12) as follows: I: G542X, R553X, W1282X, R1162X, 621-1G3 T, 1717-1G3 A, 1078⌬T, and 3659⌬C; II: ⌬F508, ⌬I507, N1303K, and S549N; III: G551Dand R560T; IV: R117H, R334W, G85E, and R347P; V: 3849ϩ5G3 A, and A455E; and unknown: 711ϩIG3 T, 2184DA, and 1898ϩIG3 A. Patients with two alleles within the same class or only one allele typed were assigned that class.…”

Section: End Point and Potential Risk Factorsmentioning

confidence: 99%

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

et al. 2008

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OBJECTIVE -Longer survival of patients with cystic fibrosis has increased the occurrence of cystic fibrosis-related diabetes (CFRD). In this study we documented the incidence of CFRD and evaluated the association between mutations responsible for cystic fibrosis and incident CFRD, while identifying potential risk factors.RESEARCH DESIGN AND METHODS -This was a population-based longitudinal study of 50 cystic fibrosis speciality clinics in the U.K. Subjects included 8,029 individuals aged 0 -64 years enrolled in the U.K. Cystic Fibrosis Registry during 1996 -2005. Of these, 5,196 with data and without diabetes were included in analyses of incidence, and 3,275 with complete data were included in analyses of risk factors. Diabetes was defined by physician diagnosis, oral glucose tolerance testing, or treatment with hypoglycemic drugs.RESULTS -A total of 526 individuals developed CFRD over 15,010 person-years. The annual incidence was 3.5%. The incidence was higher in female patients and in patients with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classes I and II. In a multivariate model of 377 cases of 3,275 patients, CFTR class (relative risk 1.70 [95% CI 1.16 -2.49], class I or II versus others), increasing age, female sex, worse pulmonary function, liver dysfunction, pancreatic insufficiency, and corticosteroid use were independently associated with incident diabetes.CONCLUSIONS -The incidence of CFRD is high in Britain. CFTR class I and II mutations increase the risk of diabetes independent of other risk factors including pancreatic exocrine dysfunction.

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“…We wished to investigate whether the detection of the T3SS and flagellin through the Ipaf-signaling pathway represents a general innate immune strategy. We chose to study Pseudomonas aeruginosa, a flagellated Gram-negative bacterium that causes disease associated with significant inflammatory responses (17,18). Much of the pathogenicity of P. aeruginosa can be traced to the expression of several virulence traits, including the synthesis of toxins, the modification of LPS (19), and the expression of the Psc T3SS.…”

mentioning

confidence: 99%

Pseudomonas aeruginosa activates caspase 1 through Ipaf

Miao

Ernst

Dors

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

272

253

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The innate immune system encodes cytosolic Nod-like receptors (NLRs), several of which activate caspase 1 processing and IL-1␤ and IL-18 secretion. Macrophages respond to Salmonella typhimurium infection by activating caspase 1 through the NLR Ipaf. This activation is mediated by cytosolic flagellin through the activity of the virulence-associated type III secretion system (T3SS). We demonstrate here that Pseudomonas aeruginosa activates caspase 1 and induces IL-1␤ secretion in infected macrophages. While live, virulent P. aeruginosa activate IL-1␤ secretion through caspase 1 and Ipaf, strains that have mutations in the T3SS or in flagellin did not. Ipaf-dependent caspase 1 activation could be recapitulated by delivering P. aeruginosa flagellin to the macrophage cytosol. We examined the role of Naip5 in P. aeruginosa-induced caspase 1 activation by using A/J (Naip5-deficient) compared with C57BL/6 and BALB/c (Naip5-sufficient) macrophages and observed that A/J macrophages secrete IL-1␤ in response to P. aeruginosa, S. typhimurium, and Listeria monocytogenes infection, as well as in response to cytosolic flagellin, but at slightly reduced levels. Thus, Ipaf-dependent detection of cytosolic flagellin is a conserved mechanism by which macrophages detect the presence of pathogens that use T3SS.flagellin ͉ inflammation ͉ type III secretion ͉ macrophage

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The Phenotypic Consequences of CFTR Mutations

Cited by 299 publications

References 78 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

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

Pseudomonas aeruginosa activates caspase 1 through Ipaf

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