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Bossard, Florian, Amal Robay, Gilles Toumaniantz, Shehrazade Dahimene, Frédéric Becq, Jean Merot y Chantal Gauthier. "NHE-RF1 protein rescues ΔF508-CFTR function". American Journal of Physiology-Lung Cellular and Molecular Physiology 292, n.º 5 (mayo de 2007): L1085—L1094. http://dx.doi.org/10.1152/ajplung.00445.2005.
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In cystic fibrosis (CF), the ΔF508-CFTR anterograde trafficking from the endoplasmic reticulum to the plasma membrane is inefficient. New strategies for increasing the delivery of ΔF508-CFTR to the apical membranes are thus pathophysiologically relevant targets to study for CF treatment. Recent studies have demonstrated that PDZ-containing proteins play an essential role in determining polarized plasma membrane expression of ionic transporters. In the present study we have hypothesized that the PDZ-containing protein NHE-RF1, which binds to the carboxy terminus of CFTR, rescues ΔF508-CFTR expression in the apical membrane of epithelial cells. The plasmids encoding ΔF508-CFTR and NHE-RF1 were intranuclearly injected in A549 or Madin-Darby canine kidney (MDCK) cells, and ΔF508-CFTR channel activity was functionally assayed using SPQ fluorescent probe. Cells injected with ΔF508-CFTR alone presented a low chloride channel activity, whereas its coexpression with NHE-RF1 significantly increased both the basal and forskolin-activated chloride conductances. This last effect was lost with ΔF508-CFTR deleted of its 13 last amino acids or by injection of a specific NHE-RF1 antisense oligonucleotide, but not by NHE-RF1 sense oligonucleotide. Immunocytochemical analysis performed in MDCK cells transiently transfected with ΔF508-CFTR further revealed that NHE-RF1 specifically determined the apical plasma membrane expression of ΔF508-CFTR but not that of a trafficking defective mutant potassium channel (KCNQ1). These data demonstrate that the modulation of the expression level of CFTR protein partners, like NHE-RF1, can rescue ΔF508-CFTR activity.
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Borkenhagen, Beatrice y Peter Prehm. "Recovery of ΔF508-CFTR Function by Citrate". Nutrients 14, n.º 20 (14 de octubre de 2022): 4283. http://dx.doi.org/10.3390/nu14204283.
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Treatment of cystic fibrosis relies so far on expensive and sophisticated drugs. A logical approach to rescuing the defective ΔF508-CFTR protein has not yet been published. Therefore, virtual docking of ATP and CFTR activators to the open conformation of the CFTR protein was performed. A new ATP binding site outside of the two known locations was identified. It was located in the cleft between the nucleotide binding domains NBD1 and NBD2 and comprised six basic amino acids in close proximity. Citrate and isocitrate were also bound to this site. Citrate was evaluated for its action on epithelial cells with intact CFTR and defective ΔF508-CFTR. It activated hyaluronan export from human breast carcinoma cells and iodide efflux, and recovered ΔF508-CFTR from premature intracellular degradation. In conclusion, citrate is an activator for ΔF508-CFTR and increases export by defective ΔF508-CFTR into the extracellular matrix of epithelial cells.
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BRADBURY, NEIL A. "Intracellular CFTR: Localization and Function". Physiological Reviews 79, n.º 1 (1 de enero de 1999): S175—S191. http://dx.doi.org/10.1152/physrev.1999.79.1.s175.
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Bradbury, Neil A. Intracellular CFTR: Localization and Function. Physiol. Rev. 79, Suppl.: S175–S191, 1999. — There is considerable evidence that CFTR can function as a chloride-selective anion channel. Moreover, this function has been localized to the apical membrane of chloride secretory epithelial cells. However, because cystic fibrosis transmembrane conductance regulator (CFTR) is an integral membrane protein, it will also be present, to some degree, in a variety of other membrane compartments (including endoplasmic reticulum, Golgi stacks, endosomes, and lysosomes). An incomplete understanding of the molecular mechanisms by which alterations in an apical membrane chloride conductance could give rise to the various clinical manifestations of cystic fibrosis has prompted the suggestion that CFTR may also play a role in the normal function of certain intracellular compartments. A variety of intracellular functions have been attributed to CFTR, including regulation of membrane vesicle trafficking and fusion, acidification of organelles, and transport of small anions. This paper aims to review the evidence for localization of CFTR in intracellular organelles and the potential physiological consequences of that localization.
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Carroll, Tiziana Piazza, Erik M. Schwiebert y William B. Guggino. "CFTR: Structure and Function". Cellular Physiology and Biochemistry 3, n.º 5-6 (1993): 388–99. http://dx.doi.org/10.1159/000154700.
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Meng, Xin, Jack Clews, Anca D. Ciuta, Eleanor R. Martin y Robert C. Ford. "CFTR structure, stability, function and regulation". Biological Chemistry 400, n.º 10 (25 de octubre de 2019): 1359–70. http://dx.doi.org/10.1515/hsz-2018-0470.
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Abstract Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette family of proteins because it has evolved into a channel. Mutations in CFTR cause cystic fibrosis, the most common genetic disease in people of European origin. The F508del mutation is found in about 90% of patients and here we present data that suggest its main effect is on CFTR stability rather than on the three-dimensional (3D) folded state. A survey of recent cryo-electron microscopy studies was carried out and this highlighted differences in terms of CFTR conformation despite similarities in experimental conditions. We further studied CFTR structure under various phosphorylation states and with the CFTR-interacting protein NHERF1. The coexistence of outward-facing and inward-facing conformations under a range of experimental conditions was suggested from these data. These results are discussed in terms of structural models for channel gating, and favour the model where the mostly disordered regulatory-region of the protein acts as a channel plug.
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Ramalho, Anabela S., Eva Fürstová, Annelotte M. Vonk, Marc Ferrante, Catherine Verfaillie, Lieven Dupont, Mieke Boon et al. "Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis". European Respiratory Journal 57, n.º 1 (3 de agosto de 2020): 1902426. http://dx.doi.org/10.1183/13993003.02426-2019.
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RationaleGiven the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF).ObjectivesTo study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.MethodsIntestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature.ResultsAcross 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.ConclusionsMeasurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.
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Londino, James D., Ahmed Lazrak, Asta Jurkuvenaite, James F. Collawn, James W. Noah y Sadis Matalon. "Influenza matrix protein 2 alters CFTR expression and function through its ion channel activity". American Journal of Physiology-Lung Cellular and Molecular Physiology 304, n.º 9 (1 de mayo de 2013): L582—L592. http://dx.doi.org/10.1152/ajplung.00314.2012.
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The human cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-activated chloride (Cl−) channel in the lung epithelium that helps regulate the thickness and composition of the lung epithelial lining fluid. We investigated whether influenza M2 protein, a pH-activated proton (H+) channel that traffics to the plasma membrane of infected cells, altered CFTR expression and function. M2 decreased CFTR activity in 1) Xenopus oocytes injected with human CFTR, 2) epithelial cells (HEK-293) stably transfected with CFTR, and 3) human bronchial epithelial cells (16HBE14o−) expressing native CFTR. This inhibition was partially reversed by an inhibitor of the ubiquitin-activating enzyme E1. Next we investigated whether the M2 inhibition of CFTR activity was due to an increase of secretory organelle pH by M2. Incubation of Xenopus oocytes expressing CFTR with ammonium chloride or concanamycin A, two agents that alkalinize the secretory pathway, inhibited CFTR activity in a dose-dependent manner. Treatment of M2- and CFTR-expressing oocytes with the M2 ion channel inhibitor amantadine prevented the loss in CFTR expression and activity; in addition, M2 mutants, lacking the ability to transport H+, did not alter CFTR activity in Xenopus oocytes and HEK cells. Expression of an M2 mutant retained in the endoplasmic reticulum also failed to alter CFTR activity. In summary, our data show that M2 decreases CFTR activity by increasing secretory organelle pH, which targets CFTR for destruction by the ubiquitin system. Alteration of CFTR activity has important consequences for fluid regulation and may potentially modify the immune response to viral infection.
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Taylor-Cousar, Jennifer L., Marcus A. Mall, Bonnie W. Ramsey, Edward F. McKone, Elizabeth Tullis, Gautham Marigowda, Charlotte M. McKee et al. "Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles". ERJ Open Research 5, n.º 2 (abril de 2019): 00082–2019. http://dx.doi.org/10.1183/23120541.00082-2019.
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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface.Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles.Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.
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Maitra, Rangan, Perumal Sivashanmugam y Keith Warner. "A Rapid Membrane Potential Assay to Monitor CFTR Function and Inhibition". Journal of Biomolecular Screening 18, n.º 9 (7 de mayo de 2013): 1132–37. http://dx.doi.org/10.1177/1087057113488420.
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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an important regulator of ion transport and fluid secretion in humans. Mutations to CFTR cause cystic fibrosis, which is a common recessive genetic disorder in Caucasians. Involvement of CFTR has been noted in other important diseases, such as secretory diarrhea and polycystic kidney disease. The assays to monitor CFTR function that have been described to date either are complicated or require specialized instrumentation and training for execution. In this report, we describe a rapid FlexStation-based membrane potential assay to monitor CFTR function. In this assay, agonist-mediated activation of CFTR results in membrane depolarization that can be monitored using a fluorescent membrane potential probe. Availability of a simple mix-and-read assay to monitor the function of this important protein might accelerate the discovery of CFTR ligands to study a variety of conditions.
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Bertrand, Carol A. y Raymond A. Frizzell. "The role of regulated CFTR trafficking in epithelial secretion". American Journal of Physiology-Cell Physiology 285, n.º 1 (julio de 2003): C1—C18. http://dx.doi.org/10.1152/ajpcell.00554.2002.
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The focus of this review is the regulated trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in distal compartments of the protein secretory pathway and the question of how changes in CFTR cellular distribution may impact on the functions of polarized epithelial cells. We summarize data concerning the cellular localization and activity of CFTR and attempt to synthesize often conflicting results from functional studies of regulated endocytosis and exocytosis in CFTR-expressing cells. In some instances, findings that are inconsistent with regulated CFTR trafficking may result from the use of overexpression systems or nonphysiological experimental conditions. Nevertheless, judging from data on other transporters, an appropriate cellular context is necessary to support regulated CFTR trafficking, even in epithelial cells. The discovery that disease mutations can influence CFTR trafficking in distal secretory and recycling compartments provides support for the concept that regulated CFTR recycling contributes to normal epithelial function, including the control of apical CFTR channel density and epithelial protein secretion. Finally, we propose molecular mechanisms for regulated CFTR endocytosis and exocytosis that are based on CFTR interactions with other proteins, particularly those whose primary function is membrane trafficking. These models provide testable hypotheses that may lead to elucidation of CFTR trafficking mechanisms and permit their experimental manipulation in polarized epithelial cells.
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Ramalho, Anabela S., Mieke Boon, Marijke Proesmans, François Vermeulen, Marianne S. Carlon y Kris Boeck. "Assays of CFTR Function In Vitro, Ex Vivo and In Vivo". International Journal of Molecular Sciences 23, n.º 3 (27 de enero de 2022): 1437. http://dx.doi.org/10.3390/ijms23031437.
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Cystic fibrosis, a multi-organ genetic disease, is characterized by abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel at the apical membrane of several epithelia. In recent years, therapeutic strategies have been developed to correct the CFTR defect. To evaluate CFTR function at baseline for diagnosis, or the efficacy of CFTR-restoring therapy, reliable tests are needed to measure CFTR function, in vitro, ex vivo and in vivo. In vitro techniques either directly or indirectly measure ion fluxes; direct measurement of ion fluxes and quenching of fluorescence in cell-based assays, change in transmembrane voltage or current in patch clamp or Ussing chamber, swelling of CFTR-containing organoids by secondary water influx upon CFTR activation. Several cell or tissue types can be used. Ex vivo and in vivo assays similarly evaluate current (intestinal current measurement) and membrane potential differences (nasal potential difference), on tissues from individual patients. In the sweat test, the most frequently used in vivo evaluation of CFTR function, chloride concentration or stimulated sweat rate can be directly measured. Here, we will describe the currently available bio-assays for quantitative evaluation of CFTR function, their indications, advantages and disadvantages, and correlation with clinical outcome measures.
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Niedermayr, Katharina, Verena Gasser, Claudia Rueckes-Nilges, Dorothea Appelt, Johannes Eder, Teresa Fuchs, Lutz Naehrlich y Helmut Ellemunter. "Personalized medicine with drugs targeting the underlying protein defect in cystic fibrosis: is monitoring of treatment response necessary?" Therapeutic Advances in Chronic Disease 13 (enero de 2022): 204062232211086. http://dx.doi.org/10.1177/20406223221108627.
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Cystic fibrosis (CF) is caused by two mutations in the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR) gene. In the last years, drugs targeting the underlying protein defect like lumacaftor/ivacaftor (LUM/IVA) or tezacaftor/ivacaftor (TEZ/IVA) and more recently elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) were admitted. Outcome parameters evaluating therapy response like forced expiratory pressure in 1 s (FEV1), body mass index (BMI) or the efficacy of CFTR function in sweat glands showed improvement in several cases. Other, CFTR biomarkers were analysed rarely. This prospective observational study was aimed at evaluating CFTR function in patients treated with different CFTR modulators together with common valid clinical outcome parameters at standardized appointments (day 0, week 2, 4, 16). We followed four patients with the same mutation ( F508del-CFTR), sex, age and disease severity. Monitoring focused on lung function, gastrointestinal aspects and CFTR function of sweat glands, nasal and intestinal epithelium. Sweat tests were performed by pilocarpine iontophoresis. Nasal potential difference (NPD) measured transepithelial voltage in vivo and potential increased when CFTR function improved. Rectal biopsies were obtained for intestinal current measurements (ICM) ex vivo. Intestinal CFTR function was assessed by stimulating chloride secretion with different reagents. Response to CFTR modulators regarding clinical outcome parameters was rather variable. A sweat chloride reduction of 35.3 mmol/L, nasal CFTR rescue of 4.4% and fivefold higher CFTR function in the intestine was seen at week 16 post-LUM/IVA. Due to our monitoring, we identified a non-responder to LUM/IVA and TEZ/IVA. In case of ELX/TEZ/IVA, clinical parameters and CFTR bioassays improved and were concordant. Although our cohort is small, results emphasize that non-responders exist and conclusions could not be drawn if patients were not monitored. Data on CFTR function can confirm or disprove ongoing CFTR dysfunction and might be helpful selectively. Non-responders need other alternative therapy options as demonstrated with ELX/TEZ/IVA.
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Souza-Menezes, Jackson, Geórgia da Silva Feltran y Marcelo M. Morales. "CFTR and TNR-CFTR expression and function in the kidney". Biophysical Reviews 6, n.º 2 (7 de mayo de 2014): 227–36. http://dx.doi.org/10.1007/s12551-014-0140-8.
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Bengtson, Charles, Neerupma Silswal, Nathalie Baumlin, Makoto Yoshida, John Dennis, Sireesha Yerrathota, Michael Kim y Matthias Salathe. "The CFTR Amplifier Nesolicaftor Rescues TGF-β1 Inhibition of Modulator-Corrected F508del CFTR Function". International Journal of Molecular Sciences 23, n.º 18 (19 de septiembre de 2022): 10956. http://dx.doi.org/10.3390/ijms231810956.
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Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have led to dramatic improvements in lung function in many people with cystic fibrosis (PwCF). However, the efficacy of CFTR modulators may be hindered by persistent airway inflammation. The cytokine transforming growth factor-beta1 (TGF-β1) is associated with worse pulmonary disease in PwCF and can diminish modulator efficacy. Thus, strategies to augment the CFTR response to modulators in an inflammatory environment are needed. Here, we tested whether the CFTR amplifier nesolicaftor (or PTI-428) could rescue the effects of TGF-β1 on CFTR function and ciliary beating in primary human CF bronchial epithelial (CFBE) cells. CFBE cells homozygous for F508del were treated with the combination of elexacaftor/tezacaftor/ivacaftor (ETI) and TGF-β1 in the presence and absence of nesolicaftor. Nesolicaftor augmented the F508del CFTR response to ETI and reversed TGF-β1-induced reductions in CFTR conductance by increasing the expression of CFTR mRNA. Nesolicaftor further rescued the reduced ciliary beating and increased expression of the cytokines IL-6 and IL-8 caused by TGF-β1. Finally, nesolicaftor augmented the F508del CFTR response to ETI in CFBE cells overexpressing miR-145, a negative regulator of CFTR expression. Thus, CFTR amplifiers, but only when used with highly effective modulators, may provide benefit in an inflamed environment.
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Valdivieso, Angel Gabriel y Tomás A. Santa-Coloma. "CFTR activity and mitochondrial function". Redox Biology 1, n.º 1 (2013): 190–202. http://dx.doi.org/10.1016/j.redox.2012.11.007.
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Bitam, Sara, Iwona Pranke, Monika Hollenhorst, Nathalie Servel, Christelle Moquereau, Danielle Tondelier, Aurélie Hatton et al. "An unexpected effect of TNF-α on F508del-CFTR maturation and function". F1000Research 4 (10 de julio de 2015): 218. http://dx.doi.org/10.12688/f1000research.6683.1.
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Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which encodes a cAMP-dependent Cl- channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular.
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Bitam, Sara, Iwona Pranke, Monika Hollenhorst, Nathalie Servel, Christelle Moquereau, Danielle Tondelier, Aurélie Hatton et al. "An unexpected effect of TNF-α on F508del-CFTR maturation and function". F1000Research 4 (2 de septiembre de 2015): 218. http://dx.doi.org/10.12688/f1000research.6683.2.
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Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which encodes a cAMP-dependent Cl- channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular.
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Blackledge, Neil P., Emma J. Carter, Joanne R. Evans, Victoria Lawson, Rebecca K. Rowntree y Ann Harris. "CTCF mediates insulator function at the CFTR locus". Biochemical Journal 408, n.º 2 (14 de noviembre de 2007): 267–75. http://dx.doi.org/10.1042/bj20070429.
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Regulatory elements that lie outside the basal promoter of a gene may be revealed by local changes in chromatin structure and histone modifications. The promoter of the CFTR (cystic fibrosis transmembrane conductance regulator) gene is not responsible for its complex pattern of expression. To identify important regulatory elements for CFTR we have previously mapped DHS (DNase I-hypersensitive sites) across 400 kb spanning the locus. Of particular interest were two DHS that flank the CFTR gene, upstream at −20.9 kb with respect to the translational start site, and downstream at +15.6 kb. In the present study we show that these two DHS possess enhancer-blocking activity and bind proteins that are characteristic of known insulator elements. The DHS core at −20.9 kb binds CTCF (CCCTC-binding factor) both in vitro and in vivo; however, the +15.6 kb core appears to bind other factors. Histone-modification analysis across the CFTR locus highlights structural differences between the −20.9 kb and +15.6 kb DHS, further suggesting that these two insulator elements may operate by distinct mechanisms. We propose that these two DHS mark the boundaries of the CFTR gene functional unit and establish a chromatin domain within which the complex profile of CFTR expression is maintained.
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Barrio, Raquel. "MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues". European Journal of Endocrinology 172, n.º 4 (abril de 2015): R131—R141. http://dx.doi.org/10.1530/eje-14-0644.
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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR).CFTRis primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet β-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either β-cell mass reduction or β-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called ‘transformational’ therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shownin vitrocapacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.
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Cao, Huibi, Hong Ouyang, Onofrio Laselva, Claire Bartlett, Zhichang Peter Zhou, Cathleen Duan, Tarini Gunawardena et al. "A helper-dependent adenoviral vector rescues CFTR to wild-type functional levels in cystic fibrosis epithelial cells harbouring class I mutations". European Respiratory Journal 56, n.º 5 (26 de mayo de 2020): 2000205. http://dx.doi.org/10.1183/13993003.00205-2020.
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Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, including the pancreas, hepatobiliary system and reproductive organs; however, lung disease is responsible for the majority of morbidity and mortality. Management of CF involves CF transmembrane conductance regulator (CFTR) modulator agents including corrector drugs to augment cellular trafficking of mutant CFTR as well as potentiators that open defective CFTR channels. These therapies are poised to help most individuals with CF, with the notable exception of individuals with class I mutations where full-length CFTR protein is not produced. For these mutations, gene replacement has been suggested as a potential solution.In this work, we used a helper-dependent adenoviral vector (HD-CFTR) to express CFTR in nasal epithelial cell cultures derived from CF subjects with class I CFTR mutations.CFTR function was significantly restored in CF cells by HD-CFTR and reached healthy control functional levels as detected by Ussing chamber and membrane potential (FLIPR) assay. A dose–response relationship was observed between the amount of vector used and subsequent functional outcomes; small amounts of HD-CFTR were sufficient to correct CFTR function. At higher doses, HD-CFTR did not increase CFTR function in healthy control cells above baseline values. This latter observation allowed us to use this vector to benchmark in vitro efficacy testing of CFTR-modulator drugs.In summary, we demonstrate the potential for HD-CFTR to inform in vitro testing and to restore CFTR function to healthy control levels in airway cells with class I or CFTR nonsense mutations.
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SCHWIEBERT, ERIK M., DALE J. BENOS, MARIE E. EGAN, M. JACKSON STUTTS y WILLIAM B. GUGGINO. "CFTR Is a Conductance Regulator as well as a Chloride Channel". Physiological Reviews 79, n.º 1 (1 de enero de 1999): S145—S166. http://dx.doi.org/10.1152/physrev.1999.79.1.s145.
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Schwiebert, Erik M., Dale J. Benos, Marie E. Egan, M. Jackson Stutts, and William B. Guggino. CFTR Is a Conductance Regulator as well as a Chloride Channel. Physiol. Rev. 79, Suppl.: S145–S166, 1999. — Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter gene family. Although CFTR has the structure of a transporter that transports substrates across the membrane in a nonconductive manner, CFTR also has the intrinsic ability to conduct Cl− at much higher rates, a function unique to CFTR among this family of ABC transporters. Because Cl− transport was shown to be lost in cystic fibrosis (CF) epithelia long before the cloning of the CF gene and CFTR, CFTR Cl− channel function was considered to be paramount. Another equally valid perspective of CFTR, however, derives from its membership in a family of transporters that transports a multitude of different substances from chemotherapeutic drugs, to amino acids, to glutathione conjugates, to small peptides in a nonconductive manner. Moreover, at least two members of this ABC transporter family ( mdr-1, SUR) can regulate other ion channels in the membrane. More simply, ABC transporters can regulate somehow the function of other cellular proteins or cellular functions. This review focuses on a plethora of studies showing that CFTR also regulates other ion channel proteins. It is the hope of the authors that the reader will take with him or her the message that CFTR is a conductance regulator as well as a Cl− channel.
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Bacalhau, Mafalda, Filipa C. Ferreira, Iris A. L. Silva, Camilla D. Buarque, Margarida D. Amaral y Miquéias Lopes-Pacheco. "Additive Potentiation of R334W-CFTR Function by Novel Small Molecules". Journal of Personalized Medicine 13, n.º 1 (1 de enero de 2023): 102. http://dx.doi.org/10.3390/jpm13010102.
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The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose–response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity.
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Alcolado, Nicole G., Dustin J. Conrad, Diogo Poroca, Mansong Li, Walaa Alshafie, Frederic G. Chappe, Ryan M. Pelis et al. "Cystic fibrosis transmembrane conductance regulator dysfunction in VIP knockout mice". American Journal of Physiology-Cell Physiology 307, n.º 2 (15 de julio de 2014): C195—C207. http://dx.doi.org/10.1152/ajpcell.00293.2013.
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Vasoactive intestinal peptide (VIP), a neuropeptide, controls multiple functions in exocrine tissues, including inflammation, and relaxation of airway and vascular smooth muscles, and regulates CFTR-dependent secretion, which contributes to mucus hydration and local innate defense of the lung. We had previously reported that VIP stimulates the VPAC1 receptor, PKCϵ signaling cascade, and increases CFTR stability and function at the apical membrane of airway epithelial cells by reducing its internalization rate. Moreover, prolonged VIP stimulation corrects the molecular defects associated with F508del, the most common CFTR mutation responsible for the genetic disease cystic fibrosis. In the present study, we have examined the impact of the absence of VIP on CFTR maturation, cellular localization, and function in vivo using VIP knockout mice. We have conducted pathological assessments and detected signs of lung and intestinal disease. Immunodetection methods have shown that the absence of VIP results in CFTR intracellular retention despite normal expression and maturation levels. A subsequent loss of CFTR-dependent chloride current was measured in functional assays with Ussing chamber analysis of the small intestine ex vivo, creating a cystic fibrosis-like condition. Interestingly, intraperitoneal administration of VIP corrected tissue abnormalities, close to the wild-type phenotype, as well as associated defects in the vital CFTR protein. The results show in vivo a primary role for VIP chronic exposure in CFTR membrane stability and function and confirm in vitro data.
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SHEPPARD, DAVID N. y MICHAEL J. WELSH. "Structure and Function of the CFTR Chloride Channel". Physiological Reviews 79, n.º 1 (1 de enero de 1999): S23—S45. http://dx.doi.org/10.1152/physrev.1999.79.1.s23.
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Sheppard, David N., and Michael J. Welsh. Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79 , Suppl.: S23–S45, 1999. — The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl− channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.
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Lotti, Virginia, Flavia Merigo, Anna Lagni, Andrea Di Clemente, Marco Ligozzi, Paolo Bernardi, Giada Rossini et al. "CFTR Modulation Reduces SARS-CoV-2 Infection in Human Bronchial Epithelial Cells". Cells 11, n.º 8 (15 de abril de 2022): 1347. http://dx.doi.org/10.3390/cells11081347.
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People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, we analyzed SARS-CoV-2 replication in wild-type and CFTR-modified human bronchial epithelial cell lines and primary cells to investigate SARS-CoV-2 infection in people with cystic fibrosis. Both immortalized and primary human bronchial epithelial cells expressing wt or F508del-CFTR along with CRISPR/Cas9 CFTR-ablated clones were infected with SARS-CoV-2 and samples were harvested before and from 24 to 72 h post-infection. CFTR function was also inhibited in wt-CFTR cells with the CFTR-specific inhibitor IOWH-032 and partially restored in F508del-CFTR cells with a combination of CFTR modulators (VX-661+VX-445). Viral load was evaluated by real-time RT-PCR in both supernatant and cell extracts, and ACE-2 expression was analyzed by both western blotting and flow cytometry. SARS-CoV-2 replication was reduced in CFTR-modified bronchial cells compared with wild-type cell lines. No major difference in ACE-2 expression was detected before infection between wild-type and CFTR-modified cells, while a higher expression in wild-type compared to CFTR-modified cells was detectable at 72 h post-infection. Furthermore, inhibition of CFTR channel function elicited significant inhibition of viral replication in cells with wt-CFTR, and correction of CFTR function in F508del-CFTR cells increased the release of SARS-CoV-2 viral particles. Our study provides evidence that CFTR expression/function is involved in the regulation of SARS-CoV-2 replication, thus providing novel insights into the role of CFTR in SARS-CoV-2 infection and the development of therapeutic strategies for COVID-19.
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Trinh, Nguyen Thu Ngan, Claudia Bilodeau, Émilie Maillé, Manon Ruffin, Marie-Claude Quintal, Martin-Yvon Desrosiers, Simon Rousseau y Emmanuelle Brochiero. "Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells". European Respiratory Journal 45, n.º 6 (18 de marzo de 2015): 1590–602. http://dx.doi.org/10.1183/09031936.00076214.
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The epithelial response to bacterial airway infection, a common feature of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied. However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to investigate its impact on ΔF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells.CFTR expression/maturation was evaluated by immunoblotting and its function by short-circuit current measurements.A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells. In CFBE-ΔF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT-325. We also confirmed a deleterious impact of PsaDM on wt-CFTR currents in non-cystic fibrosis primary airway cells as well as on the rescue of ΔF508-CFTR function induced by VRT-325 in primary cystic fibrosis cells.These findings show that CFTR function could be impaired in non-cystic fibrosis patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be affected by infectious components, which should be taken into account in screening assays of correctors.
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Silva, Iris A. L., Violeta Railean, Aires Duarte y Margarida D. Amaral. "Personalized Medicine Based on Nasal Epithelial Cells: Comparative Studies with Rectal Biopsies and Intestinal Organoids". Journal of Personalized Medicine 11, n.º 5 (16 de mayo de 2021): 421. http://dx.doi.org/10.3390/jpm11050421.
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As highly effective CFTR modulator therapies (HEMT) emerge, there is an unmet need to find effective drugs for people with CF (PwCF) with ultra-rare mutations who are too few for classical clinical trials and for whom there are no drug discovery programs. Therefore, biomarkers reliably predicting the benefit from CFTR modulator therapies are essential to find effective drugs for PwCF through personalized approaches termed theranostics. Here, we assess CFTR basal function and the individual responses to CFTR modulators in primary human nasal epithelial (pHNE) cells from PwCF carrying rare mutations and compare these measurements with those in native rectal biopsies and intestinal organoids, respectively, in the same individual. The basal function in pHNEs shows good correlation with CFTR basal function in rectal biopsies. In parallel, CFTR rescue in pHNEs by CFTR modulators correlates to that in intestinal organoids. Altogether, results show that pHNEs are a bona fide theranostic model to assess CFTR rescue by CFTR modulator drugs, in particular for PwCF and rare mutations.
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Hinata, Daichi, Ryosuke Fukuda y Tsukasa Okiyoneda. "The COPD-Associated Polymorphism Impairs the CFTR Function to Suppress Excessive IL-8 Production upon Environmental Pathogen Exposure". International Journal of Molecular Sciences 24, n.º 3 (24 de enero de 2023): 2305. http://dx.doi.org/10.3390/ijms24032305.
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COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl- channel, which is invoked in COPD. Despite the increased incidence of CFTR polymorphism R75Q or M470V in COPD patients, the mechanism of how the CFTR variant affects COPD pathogenesis remains unclear. Here, we investigated the impact of CFTR polymorphisms (R75Q, M470V) on the CFTR function in airway epithelial cell models. While wild-type (WT) CFTR suppressed the proinflammatory cytokine production induced by COPD-related pathogens including pyocyanin (PYO), R75Q- or M470V-CFTR failed. Mechanistically, the R75Q- or M470V-CFTR fractional PM activity (FPMA) was significantly lower than WT-CFTR in the presence of PYO. Notably, the CF drug Trikafta corrected the PM expression of R75Q- or M470V-CFTR even upon PYO exposure and consequently suppressed the excessive IL-8 production. These results suggest that R75Q or M470V polymorphism impairs the CFTR function to suppress the excessive proinflammatory response to environmental pathogens associated with COPD. Moreover, Trikafta may be useful to prevent the COPD pathogenesis associated with acquired CFTR dysfunction.
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Bose, Samuel J., Toby S. Scott-Ward, Zhiwei Cai y David N. Sheppard. "Exploiting species differences to understand the CFTR Cl− channel". Biochemical Society Transactions 43, n.º 5 (1 de octubre de 2015): 975–82. http://dx.doi.org/10.1042/bst20150129.
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The anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ATP-binding cassette (ABC) transporter. CFTR plays a pivotal role in transepithelial ion transport as its dysfunction in the genetic disease cystic fibrosis (CF) dramatically demonstrates. Phylogenetic analysis suggests that CFTR first appeared in aquatic vertebrates fulfilling important roles in osmosensing and organ development. Here, we review selectively, knowledge of CFTR structure, function and pharmacology, gleaned from cross-species comparative studies of recombinant CFTR proteins, including CFTR chimeras. The data argue that subtle changes in CFTR structure can affect strongly channel function and the action of CF mutations.
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Ren, Hong Yu, Diane E. Grove, Oxana De La Rosa, Scott A. Houck, Pattarawut Sopha, Fredrick Van Goor, Beth J. Hoffman y Douglas M. Cyr. "VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1". Molecular Biology of the Cell 24, n.º 19 (octubre de 2013): 3016–24. http://dx.doi.org/10.1091/mbc.e13-05-0240.
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Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.
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Graeber, Simon Y., Constanze Vitzthum y Marcus A. Mall. "Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis". Journal of Personalized Medicine 11, n.º 5 (8 de mayo de 2021): 384. http://dx.doi.org/10.3390/jpm11050384.
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Refinement of personalized treatment of cystic fibrosis (CF) with emerging medicines targeting the CF basic defect will likely benefit from biomarkers sensitive to detect improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function in individual patients. Intestinal current measurement (ICM) is a technique that enables quantitative assessment of CFTR chloride channel function in rectal tissues or other intestinal epithelia. ICM was originally developed to study the CF ion transport defect in the intestine and has been established as a sensitive biomarker of CFTR function and diagnostic test for CF. With the emergence of CFTR-directed therapeutics, ICM has become an important tool to estimate the level of rescue of CFTR function achieved by approved CFTR modulators, both at the level of CFTR genotype groups, as well as individual patients with CF. In combination with preclinical patient-derived cell culture models, ICM may aid the development of targeted therapies for patients with rare CFTR mutations. Here, we review the principles of ICM and examine how this CFTR biomarker may be used to support diagnostic testing and enhance personalized medicine for individual patients with common as well as rare CFTR mutations in the new era of medicines targeting the underlying cause of CF.
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Smith, Stephen S., Xuehong Liu, Zhi-Ren Zhang, Fang Sun, Thomas E. Kriewall, Nael A. McCarty y David C. Dawson. "Cftr". Journal of General Physiology 118, n.º 4 (1 de octubre de 2001): 407–32. http://dx.doi.org/10.1085/jgp.118.4.407.
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The goal of the experiments described here was to explore the possible role of fixed charges in determining the conduction properties of CFTR. We focused on transmembrane segment 6 (TM6) which contains four basic residues (R334, K335, R347, and R352) that would be predicted, on the basis of their positions in the primary structure, to span TM6 from near the extracellular (R334, K335) to near the intracellular (R347, R352) end. Cysteines substituted at positions 334 and 335 were readily accessible to thiol reagents, whereas those at positions 347 and 352 were either not accessible or lacked significant functional consequences when modified. The charge at positions 334 and 335 was an important determinant of CFTR channel function. Charge changes at position 334—brought about by covalent modification of engineered cysteine residues, pH titration of cysteine and histidine residues, and amino acid substitution—produced similar effects on macroscopic conductance and the shape of the I-V plot. The effect of charge changes at position 334 on conduction properties could be described by electrodiffusion or rate-theory models in which the charge on this residue lies in an external vestibule of the pore where it functions to increase the concentration of Cl adjacent to the rate-limiting portion of the conduction path. Covalent modification of R334C CFTR increased single-channel conductance determined in detached patches, but did not alter open probability. The results are consistent with the hypothesis that in wild-type CFTR, R334 occupies a position where its charge can influence the distribution of anions near the mouth of the pore.
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Fiedorczuk, Karol y Jue Chen. "Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators". Science 378, n.º 6617 (21 de octubre de 2022): 284–90. http://dx.doi.org/10.1126/science.ade2216.
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The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo–electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.
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Baldassarri, Margherita, Kristina Zguro, Valeria Tomati, Cristina Pastorino, Francesca Fava, Susanna Croci, Mirella Bruttini et al. "Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes". Cells 11, n.º 24 (16 de diciembre de 2022): 4096. http://dx.doi.org/10.3390/cells11244096.
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Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19.
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Voronkova, A. Yu, E. I. Kondratyeva, E. D. Nikolaeva, E. V. Pasnova, I. R. Fatkhullina y N. D. Odinaeva. "Pancreatitis in children with cystic fibrosis and preserved pancreatic exocrine function". Voprosy praktičeskoj pediatrii 17, n.º 3 (2022): 120–27. http://dx.doi.org/10.20953/1817-7646-2022-3-120-127.
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The pancreas is one of the main organs affected by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Pancreatitis can be a symptom of cystic fibrosis (CF) or a CFTR-related disorder. Genetic variants of the CFTR gene causing CF or having varying clinical significance are observed in 32–48% of patients. Approximately 20% of patients with mild genotypes are expected to develop pancreatitis. We report three cases of pancreatitis in children with CF and preserved pancreatic function. We focus on the challenges associated with the assessment of pancreatic insufficiency grade, suffering of children with recurrent acute and chronic pancreatitis, difficulties associated with the diagnosis and interpretation of laboratory parameters, problems of prognosis of pancreatitis development and progression in patients with pathogenic variants of the CFTR gene. Patients with mild pathogenic variants of the CFTR gene can have their pancreatic elastase-1 level reduced over time, which necessitates its annual monitoring. Patients with mild pathogenic variants should be routinely tested for pancreatic amylase, lipase, and diastase; and undergo examination using visualization methods. All CF patients require complete genotype verification to identify those with a mild genotype. Patients with recurrent pancreatitis should be checked for heterozygous pathogenic variants of the CFTR gene or CF verification. Key words: CFTR gene, cystic fibrosis, mild genotype, pancreas, pancreatitis, pancreatic elastase
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Wang, Guoshun y Hang Pong Ng. "Myeloid CFTR Loss-of-function Causes Persistent Neutrophilic Inflammation in Cystic Fibrosis". Journal of Immunology 202, n.º 1_Supplement (1 de mayo de 2019): 187.33. http://dx.doi.org/10.4049/jimmunol.202.supp.187.33.
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Abstract Persistent neutrophilic inflammation is a hallmark manifestation of cystic fibrosis (CF). However, the mechanism underlying this phenomenal clinical symptom remains incompletely understood. Here we report a pivotal role of CFTR in myeloid immune cells in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr−/−) mice and Wild-type (WT) mice were challenged peritoneally with zymosan at different doses. The lethal-dose challenge resulted in significantly higher mortality in Mye-Cftr−/− mice, indicating an intrinsic defect in host protection against inflammation in CF. The sub-lethal-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr−/− mice, reflected by persistent neutrophilic inflammation, and hyper-inflammation with significantly higher levels of pro-inflammatory cytokines, including the neutrophil-recruiting chemokines MIP-2 and KC, which led to excessive neutrophil recruitment in vivo. Pulmonary challenge with zymosan confirmed the peritoneal finding. To determine the major types of cells responsible for the over-recruitment of neutrophils, zymosan-elicited peritoneal neutrophils and macrophages from Mye-Cftr−/− and WT mice were FACS-sorted and cultured ex vivo. The CF neutrophils produced significantly more neutrophil chemokine MIP-2. Moreover, peripheral blood neutrophils and monocytes from Mye-Cftr−/− and WT mice were cultured and stimulated with zymosan in vitro. Similarly, the CF neutrophils produced significantly more MIP-2. These data altogether suggest that CFTR dysfunction in myeloid immune cells leads to excessive neutrophil recruitment, thus serving as a mechanism for the long-observed neutrophilic inflammation in CF.
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Pecho-Silva, Samuel y Ana C. Navarro-Solsol. "The c.3274T> C mutation in the CFTR gene results in bronchiectasis and loss of lung function in a 44-year-old Peruvian woman: A very rare condition". Revista Peruana de Investigación en Salud 5, n.º 2 (9 de abril de 2021): 132–35. http://dx.doi.org/10.35839/repis.5.2.1008.
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CF is an autosomal recessive disease, requiring mutations to be present in both alleles in the CF transmembrane conductance regulatory gene (CFTR). The c.3274T> C (p.Tyr1092His) mutation is not registered in the “CFTR2 project” database, but it is registered in The Human Gene Mutation Database. Neither are the two DNAAF4 c.1177C> T (p.Leu393Phe) and DNAAF5 c.1195G> A (p.Glu399Lys) mutations found in the "CFTR Project”, and their clinical consequences are currently uncertain. Here, we report the case of a Peruvian woman presenting this mutation, bronchiectasis and loss of lung function and provide a review of the literature.
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Van Goor, F., H. Yu, B. Burton, C. J. Huang y B. J. Hoffman. "WS14.1 Ivacaftor potentiates mutant CFTR forms associated with residual CFTR function". Journal of Cystic Fibrosis 11 (junio de 2012): S31. http://dx.doi.org/10.1016/s1569-1993(12)60097-6.
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Shi, Juan, Hui Li, Chao Yuan, Meihui Luo, Jun Wei y Xiaoming Liu. "Cigarette Smoke-Induced Acquired Dysfunction of Cystic Fibrosis Transmembrane Conductance Regulator in the Pathogenesis of Chronic Obstructive Pulmonary Disease". Oxidative Medicine and Cellular Longevity 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/6567578.
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Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. Cigarette smoke and oxidative stress are main etiological risks in COPD. Interestingly, recent studies suggest a considerable overlap between chronic bronchitis (CB) phenotypic COPD and cystic fibrosis (CF), a common fatal hereditary lung disease caused by genetic mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Phenotypically, CF and COPD are associated with an impaired mucociliary clearance and mucus hypersecretion, although they are two distinct entities of unrelated origin. Mechanistically, the cigarette smoke-increased oxidative stress-induced CFTR dysfunction is implicated in COPD. This underscores CFTR in understanding and improving therapies for COPD by altering CFTR function with antioxidant agents and CFTR modulators as a great promising strategy for COPD treatments. Indeed, treatments that restore CFTR function, including mucolytic therapy, antioxidant ROS scavenger, CFTR stimulator (roflumilast), and CFTR potentiator (ivacaftor), have been tested in COPD. This review article is aimed at summarizing the molecular, cellular, and clinical evidence of oxidative stress, particularly the cigarette smoke-increased oxidative stress-impaired CFTR function, as well as signaling pathways of CFTR involved in the pathogenesis of COPD, with a highlight on the therapeutic potential of targeting CFTR for COPD treatment.
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Westholm, Efraim, Anna Wendt y Lena Eliasson. "Islet Function in the Pathogenesis of Cystic Fibrosis-Related Diabetes Mellitus". Clinical Medicine Insights: Endocrinology and Diabetes 14 (enero de 2021): 117955142110312. http://dx.doi.org/10.1177/11795514211031204.
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Cystic fibrosis-related diabetes mellitus (CFRD) is the most common non-pulmonary co-morbidity in cystic fibrosis (CF). CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which leads to aberrant luminal fluid secretions in organs such as the lungs and pancreas. How dysfunctional CFTR leads to CFRD is still under debate. Both intrinsic effects of dysfunctional CFTR in hormone secreting cells of the islets and effects of exocrine damage have been proposed. In the current review, we discuss these non-mutually exclusive hypotheses with a special focus on how dysfunctional CFTR in endocrine cells may contribute to an altered glucose homeostasis. We outline the proposed role of CFTR in the molecular pathways of β-cell insulin secretion and α-cell glucagon secretion, and touch upon the importance of the exocrine pancreas and intra-pancreatic crosstalk for proper islet function.
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Degrugillier, Fanny, Abdel Aissat, Virginie Prulière-Escabasse, Lucie Bizard, Benjamin Simonneau, Xavier Decrouy, Chong Jiang, Daniela Rotin, Pascale Fanen y Stéphanie Simon. "Phosphorylation of the Chaperone-Like HspB5 Rescues Trafficking and Function of F508del-CFTR". International Journal of Molecular Sciences 21, n.º 14 (8 de julio de 2020): 4844. http://dx.doi.org/10.3390/ijms21144844.
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Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that is detected by the quality control machinery within the endoplasmic reticulum and targeted for destruction by the proteasome. Modulating quality control proteins as molecular chaperones is a promising strategy for attenuating the degradation and stabilizing the mutant CFTR at the plasma membrane. Among the molecular chaperones, the small heat shock protein HspB1 and HspB4 were shown to promote degradation of F508del-CFTR. Here, we investigated the impact of HspB5 expression and phosphorylation on transport to the plasma membrane, function and stability of F508del-CFTR. We show that a phosphomimetic form of HspB5 increases the transport to the plasma membrane, function and stability of F508del-CFTR. These activities are further enhanced in presence of therapeutic drugs currently used for the treatment of cystic fibrosis (VX-770/Ivacaftor, VX-770+VX-809/Orkambi). Overall, this study highlights the beneficial effects of a phosphorylated form of HspB5 on F508del-CFTR rescue and its therapeutic potential in cystic fibrosis.
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Hwang, Tzyh-Chang, Jiunn-Tyng Yeh, Jingyao Zhang, Ying-Chun Yu, Han-I. Yeh y Samantha Destefano. "Structural mechanisms of CFTR function and dysfunction". Journal of General Physiology 150, n.º 4 (26 de marzo de 2018): 539–70. http://dx.doi.org/10.1085/jgp.201711946.
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Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) chloride channel plays a critical role in regulating transepithelial movement of water and electrolyte in exocrine tissues. Malfunction of the channel because of mutations of the cftr gene results in CF, the most prevalent lethal genetic disease among Caucasians. Recently, the publication of atomic structures of CFTR in two distinct conformations provides, for the first time, a clear overview of the protein. However, given the highly dynamic nature of the interactions among CFTR’s various domains, better understanding of the functional significance of these structures requires an integration of these new structural insights with previously established biochemical/biophysical studies, which is the goal of this review.
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Prins, Stella, Emily Langron, Cato Hastings, Emily J. Hill, Andra C. Stefan, Lewis D. Griffin y Paola Vergani. "Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity". Journal of Biological Chemistry 295, n.º 49 (15 de septiembre de 2020): 16529–44. http://dx.doi.org/10.1074/jbc.ra120.014061.
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The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.
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Bai, Yonghong, Min Li y Tzyh-Chang Hwang. "Structural basis for the channel function of a degraded ABC transporter, CFTR (ABCC7)". Journal of General Physiology 138, n.º 5 (31 de octubre de 2011): 495–507. http://dx.doi.org/10.1085/jgp.201110705.
Texto completoResumen
Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily, but little is known about how this ion channel that harbors an uninterrupted ion permeation pathway evolves from a transporter that works by alternately exposing its substrate conduit to the two sides of the membrane. Here, we assessed reactivity of intracellularly applied thiol-specific probes with cysteine residues substituted into the 12th transmembrane segment (TM12) of CFTR. Our experimental data showing high reaction rates of substituted cysteines toward the probes, strong blocker protection of cysteines against reaction, and reaction-induced alterations in channel conductance support the idea that TM12 of CFTR contributes to the lining of the ion permeation pathway. Together with previous work, these findings raise the possibility that pore-lining elements of CFTR involve structural components resembling those that form the substrate translocation pathway of ABC transporters. In addition, comparison of reaction rates in the open and closed states of the CFTR channel leads us to propose that upon channel opening, the wide cytoplasmic vestibule tightens and the pore-lining TM12 rotates along its helical axis. This simple model for gating conformational changes in the inner pore domain of CFTR argues that the gating transition of CFTR and the transport cycle of ABC proteins share analogous conformational changes. Collectively, our data corroborate the popular hypothesis that degradation of the cytoplasmic-side gate turned an ABC transporter into the CFTR channel.
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Weber, Adam J., Grace Soong, Ruth Bryan, Shahryar Saba y Alice Prince. "Activation of NF-κB in airway epithelial cells is dependent on CFTR trafficking and Cl− channel function". American Journal of Physiology-Lung Cellular and Molecular Physiology 281, n.º 1 (1 de julio de 2001): L71—L78. http://dx.doi.org/10.1152/ajplung.2001.281.1.l71.
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Polymorphonuclear leukocyte-dominated airway inflammation is a major component of cystic fibrosis (CF) lung disease and may be associated with CF transmembrane conductance regulator (CFTR) dysfunction as well as infection. Mutant ΔF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause “cell stress” and activation of nuclear factor (NF)-κB. G551D mutants also lack Cl− channel function, but CFTR is trafficked normally. We compared the effects of CFTR mutations on the endogenous activation of an NF-κB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked ΔF508 allele caused a sevenfold activation of NF-κB compared with wild-type CFTR or the G551D mutant ( P < 0.001). NF-κB was also activated in 9/HTEo−/pCep-R cells and in 16HBE/p cftrantisense cell lines, which lack CFTR Cl− channel function but do not accumulate mutant protein in the ER. This endogenous activation of NF-κB was associated with elevated interleukin-8 expression. Impaired CFTR Cl− channel activity as well as cell stress due to accumulation of mistrafficked CFTR in the ER contributes to the endogenous activation of NF-κB in cells with the CFTR mutation.
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Fuller, C. M. y D. J. Benos. "CFTR!" American Journal of Physiology-Cell Physiology 263, n.º 2 (1 de agosto de 1992): C267—C286. http://dx.doi.org/10.1152/ajpcell.1992.263.2.c267.
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Cystic fibrosis (CF) is a fatal genetic disease primarily affecting Caucasians, although cases have been reported from other ethnic groups. CF has a complex etiology, but it is chiefly a disease of electrolyte transport and is characterized by defects in fluid secretion by several epithelia, including the sweat duct, exocrine pancreas, and the pulmonary airways. The link between CF and a defect in cAMP-mediated Cl- transport in secretory epithelia was established in the early 1980s. Since then, numerous electrophysiological studies have focused on the characterization and regulation of individual Cl- channels underlying the macroscopic Cl- currents of secretory epithelia in the airways, sweat ducts, and gut. In this review the results of these studies in the light of current knowledge of the function of the CF gene product, the CF transmembrane conductance regulator (CFTR) protein, will be analyzed. The CFTR protein is a member of a family of ATP-binding proteins that act as unidirectional solute pumps. These proteins are membrane spanning, are found in both prokaryotic and eukaryotic cells, and have two ATP-binding domains. The family includes the p-glycoproteins that are involved with the expression of multidrug resistance in certain tumor cells. The majority of CF chromosomes (70%) have a single codon deletion that translates to a missing phenylalanine residue at position 508 (delta F508) of the protein. Unique for this family of proteins, the CFTR protein possesses an additional highly charged domain (the R domain) containing several consensus polypeptide sequences for kinase phosphorylation. Although CFTR bears structural resemblance to this family of ATP-dependent pumps, overexpression of the protein in a variety of different cell types is associated with the appearence of a cAMP-sensitive Cl- channel. We critically examine current information concerning the structure-function relationships of the CFTR protein obtained from both electrophysiological and biochemical approaches. We also summarize recent evidence suggesting that the CFTR protein may act as a pump and a channel, a hypothesis in keeping with the multifaceted nature of the disease.
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Angyal, Dora, Marcel J. C. Bijvelds, Marco J. Bruno, Maikel P. Peppelenbosch y Hugo R. de Jonge. "Bicarbonate Transport in Cystic Fibrosis and Pancreatitis". Cells 11, n.º 1 (24 de diciembre de 2021): 54. http://dx.doi.org/10.3390/cells11010054.
Texto completoResumen
CFTR, the cystic fibrosis (CF) gene-encoded epithelial anion channel, has a prominent role in driving chloride, bicarbonate and fluid secretion in the ductal cells of the exocrine pancreas. Whereas severe mutations in CFTR cause fibrosis of the pancreas in utero, CFTR mutants with residual function, or CFTR variants with a normal chloride but defective bicarbonate permeability (CFTRBD), are associated with an enhanced risk of pancreatitis. Recent studies indicate that CFTR function is not only compromised in genetic but also in selected patients with an acquired form of pancreatitis induced by alcohol, bile salts or smoking. In this review, we summarize recent insights into the mechanism and regulation of CFTR-mediated and modulated bicarbonate secretion in the pancreatic duct, including the role of the osmotic stress/chloride sensor WNK1 and the scaffolding protein IRBIT, and current knowledge about the role of CFTR in genetic and acquired forms of pancreatitis. Furthermore, we discuss the perspectives for CFTR modulator therapy in the treatment of exocrine pancreatic insufficiency and pancreatitis and introduce pancreatic organoids as a promising model system to study CFTR function in the human pancreas, its role in the pathology of pancreatitis and its sensitivity to CFTR modulators on a personalized basis.
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Uliyakina, Inna, Hugo M. Botelho, Ana C. da Paula, Sara Afonso, Miguel J. Lobo, Verónica Felício, Carlos M. Farinha y Margarida D. Amaral. "Full Rescue of F508del-CFTR Processing and Function by CFTR Modulators Can Be Achieved by Removal of Two Regulatory Regions". International Journal of Molecular Sciences 21, n.º 12 (25 de junio de 2020): 4524. http://dx.doi.org/10.3390/ijms21124524.
Texto completoResumen
Cystic Fibrosis (CF) is caused by mutations in the CF Transmembrane conductance Regulator (CFTR), the only ATP-binding cassette (ABC) transporter functioning as a channel. Unique to CFTR is a regulatory domain which includes a highly conformationally dynamic region—the regulatory extension (RE). The first nucleotide-binding domain of CFTR contains another dynamic region—regulatory insertion (RI). Removal of RI rescues the trafficking defect of CFTR with F508del, the most common CF-causing mutation. Here we aimed to assess the impact of RE removal (with/without RI or genetic revertants) on F508del-CFTR trafficking and how CFTR modulator drugs VX-809/lumacaftor and VX-770/ivacaftor rescue these variants. We generated cell lines expressing ΔRE and ΔRI CFTR (with/without genetic revertants) and assessed CFTR expression, stability, plasma membrane levels, and channel activity. Our data demonstrated that ΔRI significantly enhanced rescue of F508del-CFTR by VX-809. While the presence of the RI seems to be precluding full rescue of F508del-CFTR processing by VX-809, this region appears essential to rescue its function by VX-770, suggesting some contradictory role in rescue of F508del-CFTR by these two modulators. This negative impact of RI removal on VX-770-stimulated currents on F508del-CFTR can be compensated by deletion of the RE which also leads to the stabilization of this mutant. Despite both regions being conformationally dynamic, RI precludes F508del-CFTR processing while RE affects mostly its stability and channel opening.
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Sousa, Luis, Ines Pankonien, Luka A. Clarke, Iris Silva, Karl Kunzelmann y Margarida D. Amaral. "KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway". Cells 9, n.º 7 (2 de julio de 2020): 1607. http://dx.doi.org/10.3390/cells9071607.
Texto completoResumen
Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
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Shin, Yonghwan, Minkyoung Kim, Jonghwa Won, Junchul Kim, Seog Bae Oh, Jong-Ho Lee y Kyungpyo Park. "Epigenetic Modification of CFTR in Head and Neck Cancer". Journal of Clinical Medicine 9, n.º 3 (9 de marzo de 2020): 734. http://dx.doi.org/10.3390/jcm9030734.
Texto completoResumen
Cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, is critical for secretion and absorption across diverse epithelia. Mutations or absence of CFTR result in pathogeneses, including cancer. While CFTR has been proposed as a tumor suppressing gene in tumors of the intestine, lung, and breast cancers, its effects in head and neck cancer (HNC) have yet to be investigated. This study aimed to define expression patterns and epigenetic modifications of CFTR in HNC. CFTR was expressed in normal but not in HNC cells and tissues. Treatment with 5-aza-2′-deoxycytidine (5-Aza-CdR) was associated with rescued expression of CFTR, whose function was confirmed by patch clamp technique. Further experiments demonstrated that CFTR CpG islands were hypermethylated in cancer cells and tissues and hypomethylated in normal cells and tissue. Our results suggest that CFTR epigenetic modifications are critical in both down-regulation and up-regulation of CFTR expression in HNC and normal cells respectively. We then investigated the impact of CFTR on expressions and functions of cancer-related genes. CFTR silencing was closely associated with changes to other cancer-related genes, suppressing apoptosis while enhancing proliferation, cell motility, and invasion in HNC. Our findings demonstrate that hypermethylation of CFTR CpG islands and CFTR deficiency is closely related to HNC.