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The Cystic Fibrosis Transmembrane Regulator (CFTR) in the kidney
MORALES, MARCELO M.;FALKENSTEIN, DORIS;LOPES, ANíBAL GIL;
Anais da Academia Brasileira de Ciências , 2000, DOI: 10.1590/S0001-37652000000300013
Abstract: the cystic fibrosis transmembrane regulator (cftr) is a cl - channel. mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the cystic fibrosis disease (cf). in spite of the high expression of cftr in the kidney, patients with cf do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. cftr mrna is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (ccd) and medullary (imcd) collecting ducts. several studies have demonstrated that cftr does not only transport cl - but also secretes atp and, thus, controls other conductances such as na+ (enac) and k+ (romk2) channels, especially in ccd. in the polycystic kidney the secretion of chloride through cftr contributes to the cyst enlargement. this review is focused on the role of cftr in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.
The Cystic Fibrosis Transmembrane Regulator (CFTR) in the kidney  [cached]
MORALES MARCELO M.,FALKENSTEIN DORIS,LOPES ANíBAL GIL
Anais da Academia Brasileira de Ciências , 2000,
Abstract: The cystic fibrosis transmembrane regulator (CFTR) is a Cl- channel. Mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the Cystic Fibrosis disease (CF). In spite of the high expression of CFTR in the kidney, patients with CF do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. CFTR mRNA is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (CCD) and medullary (IMCD) collecting ducts. Several studies have demonstrated that CFTR does not only transport Cl- but also secretes ATP and, thus, controls other conductances such as Na+ (ENaC) and K+ (ROMK2) channels, especially in CCD. In the polycystic kidney the secretion of chloride through CFTR contributes to the cyst enlargement. This review is focused on the role of CFTR in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.
Characterization of Defects in Ion Transport and Tissue Development in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Knockout Rats  [PDF]
Katherine L. Tuggle, Susan E. Birket, Xiaoxia Cui, Jeong Hong, Joe Warren, Lara Reid, Andre Chambers, Diana Ji, Kevin Gamber, Kengyeh K. Chu, Guillermo Tearney, Li Ping Tang, James A. Fortenberry, Ming Du, Joan M. Cadillac, David M. Bedwell, Steven M. Rowe, Eric J. Sorscher, Michelle V. Fanucchi
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091253
Abstract: Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/?) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR?/?) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR?/? rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR?/? males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR?/? animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.
Relating the Disease Mutation Spectrum to the Evolution of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)  [PDF]
Lavanya Rishishwar, Neha Varghese, Eishita Tyagi, Stephen C. Harvey, I. King Jordan, Nael A. McCarty
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042336
Abstract: Cystic fibrosis (CF) is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR) protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease-causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum. Site-specific evolutionary constraint values from the widely used comparative method PolyPhen2 show the best correlation with the CFTR mutation score spectrum, whereas more straightforward conservation based measures (ConSurf and ScoreCons) show the greatest ability to predict individual CFTR disease-causing mutations. While far greater than could be expected by chance alone, the fraction of the variability in mutation scores explained by the PolyPhen2 metric (3.6%), along with the best set of paired sensitivity (58%) and specificity (60%) values for the prediction of disease-causing residues, were marginal. These data indicate that evolutionary constraint levels are informative but far from determinant with respect to disease-causing mutations in CFTR. Nevertheless, this work shows that, when combined with additional lines of evidence, information on site-specific evolutionary conservation can and should be used to guide site-directed mutagenesis experiments by more narrowly defining the set of target residues, resulting in a potential savings of both time and money.
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Allelic Variants Relate to Shifts in Faecal Microbiota of Cystic Fibrosis Patients  [PDF]
Serena Schippa, Valerio Iebba, Floriana Santangelo, Antonella Gagliardi, Riccardo Valerio De Biase, Antonella Stamato, Serenella Bertasi, Marco Lucarelli, Maria Pia Conte, Serena Quattrucci
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061176
Abstract: Introduction In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF). CFTR mutations (F508del is the most common) lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. Methods Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. Results Patients were classified by two different criteria: 1) presence/absence of F508del mutation; 2) disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme) were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum) were reduced. Conclusions This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a ‘systemic disease’, linking the lung and the gut in a joined axis.
Human Amnion Epithelial Cells Induced to Express Functional Cystic Fibrosis Transmembrane Conductance Regulator  [PDF]
Sean V. Murphy, Rebecca Lim, Philip Heraud, Marian Cholewa, Mark Le Gros, Martin D. de Jonge, Daryl L. Howard, David Paterson, Courtney McDonald, Anthony Atala, Graham Jenkin, Euan M. Wallace
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046533
Abstract: Cystic fibrosis, an autosomal recessive disorder caused by a mutation in a gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), remains a leading cause of childhood respiratory morbidity and mortality. The respiratory consequences of cystic fibrosis include the generation of thick, tenacious mucus that impairs lung clearance, predisposing the individual to repeated and persistent infections, progressive lung damage and shortened lifespan. Currently there is no cure for cystic fibrosis. With this in mind, we investigated the ability of human amnion epithelial cells (hAECs) to express functional CFTR. We found that hAECs formed 3-dimensional structures and expressed the CFTR gene and protein after culture in Small Airway Growth Medium (SAGM). We also observed a polarized CFTR distribution on the membrane of hAECs cultured in SAGM, similar to that observed in polarized airway cells in vivo. Further, hAECs induced to express CFTR possessed functional iodide/chloride (I?/Cl?) ion channels that were inhibited by the CFTR-inhibitor CFTR-172, indicating the presence of functional CFTR ion channels. These data suggest that hAECs may be a promising source for the development of a cellular therapy for cystic fibrosis.
Functional Interactions of HCO3- with Cystic Fibrosis Transmembrane Conductance Regulator  [cached]
Gray MA,O'Reilly C,Winpenny J,Argent BE
JOP Journal of the Pancreas , 2001,
Abstract: Disruption of normal cystic fibrosis transmembrane conductance regulator- (CFTR)-mediated Cl(-) transport is associated with cystic fibrosis (CF). CFTR is also required for HCO(3)(-) transport in many tissues such as the lungs, gastro-intestinal tract, and pancreas, although the exact role CFTR plays is uncertain. Given the importance of CFTR in HCO(3)(-) transport by so many CF-affected organ systems, it is perhaps surprising that relatively little is known about the interactions of HCO(3)(-) ions with CFTR. We have used patch clamp recordings from native pancreatic duct cells to study HCO(3)(-) permeation and interaction with CFTR. Ion selectivity studies shows that CFTR is between 3-5 times more selective for Cl(-) over HCO(3)(-). In addition, extracellular HCO(3)(-) has a novel inhibitory effect on cAMP-stimulated CFTR currents carried by Cl(-). The block by HCO(3)(-) was rapid, relatively independent of voltage and occurred over the physiological range of HCO(3)(-) concentrations. These data show that luminal HCO(3)(-) acts as a potent regulator of CFTR, and suggests that inhibition involves an external anion-binding site on the channel. This work has implications not only for elucidating mechanisms of HCO(3)(-) transport in epithelia, but also for approaches used to treat CF.
CFTR Depletion Results in Changes in Fatty Acid Composition and Promotes Lipogenesis in Intestinal Caco 2/15 Cells  [PDF]
Geneviève Mailhot,Rémi Rabasa-Lhoret,Alain Moreau,Yves Berthiaume,Emile Levy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010446
Abstract: Abnormal fatty acid composition (FA) in plasma and tissue lipids frequently occurs in homozygous and even in heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The mechanism(s) underlying these abnormalities remained, however, poorly understood despite the potentially CFTR contributing role.
Defective CFTR Expression and Function Are Detectable in Blood Monocytes: Development of a New Blood Test for Cystic Fibrosis  [PDF]
Claudio Sorio,Mario Buffelli,Chiara Angiari,Michele Ettorre,Jan Johansson,Marzia Vezzalini,Laura Viviani,Mario Ricciardi,Genny Verzè,Baroukh Maurice Assael,Paola Melotti
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022212
Abstract: Evaluation of cystic fibrosis transmembrane conductance regulator (CFTR) functional activity to assess new therapies and define diagnosis of cystic fibrosis (CF) is cumbersome. It is known that leukocytes express detectable levels of CFTR but the molecule has not been characterized in these cells. In this study we aim at setting up and validating a blood test to evaluate CFTR expression and function in leukocytes.
Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis  [cached]
Nico Derichs
European Respiratory Review , 2013,
Abstract: 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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