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Provided herein are bioactive agents comprising a compound that inhibits the ion transport activity of a cystic fibrosis transmembrane conductance regulator (CFTR) and that is linked to a macromolecule that interacts with a cell that expresses CFTR. The bioactive agents described herein are useful for treating diseases, disorders, and sequelae of diseases, disorders, and conditions that are associated with aberrantly increased CFTR activity, for example, secretory diarrhea.
TY - JOUR. T1 - Intracellular cysteines of the cystic fibrosis transmembrane conductance regulator (CFTR) modulate channel gating. AU - Ketchum, Christian. AU - Yue, Hongwen. AU - Alessi, Karen. AU - Devidas, Shreenivas. AU - Guggino, William. AU - Maloney, Peter. PY - 2002/1/1. Y1 - 2002/1/1. N2 - The cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette superfamily, is a cAMP-activated chloride channel. CFTR contains two transmembrane domains (TMDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. We found that whole-cell CFTR-dependent Cl - currents in Xenopus laevis oocytes were sensitive to HgCl 2 , suggesting that modification of endogenous cysteines alters channel activity. To understand better this phenomenon, site-directed mutagenesis was employed to generate both individual cysteine replacements and a version of the molecule with no cysteines in the hydrophobic sector. Each mutant displayed a forskolin/IBMX-activated ...
Read "Interactions between Impermeant Blocking Ions in the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore: Evidence for Anion-Induced Conformational Changes, The Journal of Membrane Biology" on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
We wish to construct a mouse model for the human inherited disease cystic fibrosis. We describe here the successful targeting in embryonal stem cells of the murine homologue (Cftr) of the cystic fibrosis transmembrane conductance regulator gene, as the first critical step towards this end. The targeting event precisely disrupts exon 10, the site of the major mutation in patients with cystic fibrosis. The targeted cells are pluripotent and competent to form chimaeras.
TY - JOUR. T1 - Cystic fibrosis transmembrane conductance regulator. T2 - The NBF1 + R (nucleotide-binding fold 1 and regulatory domain) segment acting alone catalyses a Co2+/Mn2+/Mg2+-ATPase activity markedly inhibited by both Cd2+ and the transition-state analogue orthovanadate. AU - Annereau, Jean Philippe. AU - Ko, Young Hee. AU - Pedersen, Peter L.. PY - 2003/4/15. Y1 - 2003/4/15. N2 - Cystic fibrosis (CF) is caused by mutations in the gene encoding CFTR (cystic fibrosis transmembrane conductance regulator), a regulated anion channel and member of the ATP-binding-cassette transporter (ABC transporter) superfamily. Of CFTRs five domains, the first nucleotide-binding fold (NBF1) has been of greatest interest both because it is the major hotspot for mutations that cause CF, and because it is connected to a unique regulatory domain (R). However, attempts have failed to obtain a catalytically active NBF1 + R protein in the absence of a fusion partner. Here, we report that such a protein can ...
We developed molecular models for the cystic fibrosis transmembrane conductance regulator chloride channel based on the prokaryotic ABC transporter, Sav1866. Here we analyze predicted pore geometry and side-chain orientations for TM3, TM6, TM9, and TM12, with particular attention being paid to the location of the rate-limiting barrier for anion conduction. Side-chain orientations assayed by cysteine scanning were found to be from 77 to 90% in accord with model predictions. The predicted geometry of the anion conduction path was defined by a space-filling model of the pore and confirmed by visualizing the distribution of water molecules from a molecular dynamics simulation. The pore shape is that of an asymmetric hourglass, comprising a shallow outward-facing vestibule that tapers rapidly toward a narrow bottleneck linking the outer vestibule to a large inner cavity extending toward the cytoplasmic extent of the lipid bilayer. The junction between the outer vestibule and the bottleneck features an
Cystic fibrosis transmembrane conductance regulator (CFTR) has been considered to be involved in the regulatory pathway of biliary mucin secretion. We investigated expression of CFTR protein and mRNA in 24 livers with hepatolithiasis, in 6 with cholangiocarcinoma, and in 12 histologically normal livers. According to the histologic features of chronic proliferative cholangitis, hepatolithiasis was subdivided into inflammatory cell infiltration predominant (N = 14) and fibrosis predominant (N = 10). The mean signal density of CFTR in overall hepatolithiasis and in histologically normal livers was 1.23 ± 0.15 and 1.01 ± 0.13, respectively (P | 0.05). The CFTR protein (1.60 ± 0.18) and mRNA (1.09 ± 0.15) in inflammatory cell infiltration predominant patients were significantly higher (CFTR protein, 1.01 ± 0.13; mRNA, 0.75 ± 0.11) than in control subjects (P | 0.05), whereas those in fibrosis-predominant patients (CFTR protein, 0.72 ± 0.15; mRNA, 0.55 ± 0.13) were less than in control subjects (P | 0
The olfactory epithelium (OE) of mice deficient in cystic fibrosis transmembrane conductance regulator (CFTR) exhibits ion transport deficiencies reported in human CF airways, as well as progressive neuronal loss, suggesting defects in olfactory neuron homeostasis. Microvillar cells, a specialized OE cell-subtype, have been implicated in maintaining tissue homeostasis. These cells are endowed with a PLCβ2/IP3 R3/TRPC6 signal transduction pathway modulating release of neuropeptide Y (NPY), which stimulates OE stem cell activity. It is unknown, however, whether microvillar cells also mediate the deficits observed in CFTR-null mice. Here we show that Cftr mRNA in mouse OE is exclusively localized in microvillar cells and CFTR immunofluorescence is coassociated with the scaffolding protein NHERF-1 and PLCβ2 in microvilli. In CFTR-null mice, PLCβ2 was undetectable, NHERF-1 mislocalized, and IP3 R3 more intensely stained, along with increased levels of NPY, suggesting profound alteration of the ...
Deletion of phenylalanine 508 (delta Phe-508) in the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes approximately 70% of all cases of cystic fibrosis. This residue lies in a region of the protein that we have synthesized chemically and shown to bind adenine nucleotides (Th …
Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis Academic Article ...
Structural information is required to define the molecular basis for chloride conduction through CFTR (cystic fibrosis transmembrane conductance regulator). Towards this goal, we expressed MSD2, the second of the two MSDs (membrane-spanning domains) of CFTR, encompassing residues 857-1158 in Sf9 cells using the baculovirus system. In Sf9 plasma membranes, MSD2 migrates as expected for a dimer in non-dissociative PAGE, and confers the appearance of an anion permeation pathway suggesting that dimeric MSD2 mediates anion flux. To assess directly the function and quaternary structure of MSD2, we purified it from Sf9 cells by virtue of its polyhistidine tag and nickel affinity. Reconstitution of MSD2 into liposomes conferred a 4,4′-di-isothiocyanostilbene-2,2′-disulphonate-inhibitable, chloride-selective electrodiffusion pathway. Further, this activity is probably mediated directly by MSD2 as reaction of its single cysteine residue (Cys866) with the thiol modifying reagent, ...
The level of the mature native 170 kDa form of CFTR (cystic fibrosis transmembrane conductance regulator) at the plasma membrane is under the control of a selective proteolysis catalysed by calpain. The product of this limited digestion, consisting of discrete fragments still associated by strong interactions, is removed from the plasma membrane and internalized in vesicles and subject to an additional degradation. This process can be monitored by visualizing the accumulation of a 100 kDa fragment in a proliferating human leukaemic T-cell line and in human circulating lymphocytes. In reconstructed systems, and in intact cells, the conversion of native CFTR into the 100 kDa fragment linearly correlated with calpain activation and was prevented by addition of synthetic calpain inhibitors. A reduction in Ca2+ influx, by blocking the NMDA (N-methyl-D-aspartate) receptor Ca2+ channel, inhibited the conversion of the native 170 kDa fragment into the 100 kDa fragment, whereas an endosome acidification ...
cAMP-Protein Kinase A Activates Cystic Fibrosis Transmembrane Conductance Regulator for ATP Release from Rat Skeletal Muscle during Low pH or Contractions. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Function and Expression of Cystic Fibrosis Transmembrane Conductance Regulator after Small Intestinal Transplantation in Mice. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Cystic fibrosis (CF) is the most common autosomal, recessive, life-span shortening disease in Caucasians. Since discovery of the gene for CF (cystic fibrosis transmembrane conductance regulator [CFTR]) in 1989, knowledge of the molecular function of this gene and its interactions has offered new the …
Cystic fibrosis (CF) is a progressive life threatening multisystem genetic disease which affects the CF transmembrane conductance regulator channel. Respiratory causes remain the most common mortality in CF. With the onset of newborn screening, initiating treatments both for prophylaxis and disease management, optimizing nutritional support, and developing therapies targeting CF transmembrane conductance regulator protein, this has significantly changed the face of managing this devastating disease. Bronchoscopy and related procedures such as bronchoalveolar lavage (BAL), transbronchial biopsies, and protected brush sampling have been looked at in the management of CF as patients with CF continue to live longer with the help of newer therapies, the microbiome in the lung becomes less diverse along with increased occurrences for noninfectious causes of airway diseases ...
A cAMP-inducible chloride permeability has been detected in mouse fibroblast (L cell) lines upon stable integration of a full-length cDNA encoding the human cystic fibrosis transmembrane conductance regulator (CFTR). As indicated by a Cl--indicator dye, the Cl- permeability of the plasma membrane increases by 10- to 30-fold within 2 min after treatment of the cells with forskolin, an activator of adenylyl cyclase. The properties of the conductance are similar to those described in secretory epithelial cells; the whole-cell current-voltage relationship is linear and there is no evidence of voltage-dependent inactivation or activation. In contrast, this cAMP-dependent Cl- flux is undetectable in the untransfected cells or cells harboring defective cDNA constructs, including one with a phenylalanine deletion at amino acid position 508 (ΔF508), the most common mutation causing cystic fibrosis. These observations are consistent with the hypothesis that the CFTR is a cAMP-dependent Cl- channel. The ...
Cystic fibrosis (CF) is a genetic defect in the cystic fibrosis transmembrane conductance regulator protein and is the most common life-limiting genetic condition affecting the Caucasian population. It is an autosomal recessive, monogenic inherited disorder characterized by failure of airway host defense against bacterial infection, which results in bronchiectasis, the breakdown of airway wall extracellular matrix (ECM). In this study, we show that the in vitro models consisting of human tracheo-bronchial-epithelial (hBE) cells grown on porous supports with embedded magnetic nanoparticles (MNPs) at an air-liquid interface are suitable for long term, non-invasive assessment of ECM remodeling using magnetomotive optical coherence elastography (MMOCE). The morphology of ex vivo CF and normal lung tissues using OCT and correlative study with histology is also examined. We also demonstrate a quantitative measure of normal and CF airway elasticity using MMOCE. The improved understanding of pathologic ...
Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a ...
The effects of a thiazolidinone derivative, 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (or CFTRinh-172), on cystic fibrosis transmembrane conductance regulator (CFTR) gating were studied in excised inside-out membrane patches from Chinese hamster ovary cells transiently expressing wild-type and mutant CFTR. We found that the application of CFTRinh-172 results in an increase of the mean closed time and a decrease of the mean open time of the channel. A hyperbolic relationship between the closing rate and [CFTRinh-172] suggests that CFTRinh-172 does not act as a simple pore blocker. Interestingly, the potency of inhibition increases as the open time of the channel is increased with an IC50 in the low nanomolar range for CFTR channels locked in an open state for tens of seconds. Our studies also provide evidence that CFTRinh-172 can bind to both the open state and the closed state. However, at least one additional step, presumably reflecting ...
Author summary Synonymous single nucleotide polymorphisms (sSNPs) occur at high frequency in the human genome and are associated with ~50 diseases in humans; the responsible molecular mechanisms remain enigmatic. Here, we investigate the impact of the common sSNP, T2562G, on cystic fibrosis transmembrane conductance regulator (CFTR). Although this sSNP, by itself, does not cause cystic fibrosis (CF), it is prevalent in patients with CFTR-related disorders. T2562G sSNP modifies the local translation speed at the Thr854 codon, leading to changes in CFTR stability and channel function. This sSNP introduces a codon pairing to a low-abundance tRNA, which is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting a tissue-specific effect of this sSNP. Enhancement of the cellular concentration of the tRNA cognate to the mutant ACG codon rescues the stability and conduction defects of T2562G-CFTR. These findings reveal an unanticipated mechanism-inverting the programmed local
臺大位居世界頂尖大學之列,為永久珍藏及向國際展現本校豐碩的研究成果及學術能量,圖書館整合機構典藏(NTUR)與學術庫(AH)不同功能平台,成為臺大學術典藏NTU scholars。期能整合研究能量、促進交流合作、保存學術產出、推廣研究成果。. To permanently archive and promote researcher profiles and scholarly works, Library integrates the services of "NTU Repository" with "Academic Hub" to form NTU Scholars.. ...
Трансмембранный регулятор муковисцидоза (англ. CFTR - Cystic Fibrosis Transmembrane conductance Regulator) - белок, участвующий в транспорте ионов хлора через мембрану клетки, а также название гена, кодирующего этот белок. Ген CFTR находится на длинном плече 7-й хромосомы. Мутации в гене CFTR приводят к возникновению заболевания муковисцидоз, а также могут быть причиной мужского бесплодия. Наиболее часто встречается мутация ΔF508 (более 50 % из всех выявляемых мутаций гена), при которой происходит делеция остатка фенилаланина-508 из полипептидной цепочки, что приводит к нарушению ...
J Biol Chem. 1995 Jan 27;270(4):1711-7. Comparative Study; Research Support, Non-U.S. Govt; Research Support, U.S. Govt, P.H.S.
Sigma-Aldrich offers abstracts and full-text articles by [Chatchai Muanprasat, Lalida Sirianant, Sunhapas Soodvilai, Ratchanaporn Chokchaisiri, Apichart Suksamrarn, Varanuj Chatsudthipong].
1CKY: Cystic fibrosis transmembrane conductance regulator: solution structures of peptides based on the Phe508 region, the most common site of disease-causing DeltaF508 mutation.
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EDITOR,-Cystic fibrosis is the most common serious autosomal recessive condition in white populations, affecting about 1 in 2500 live births, and until recently life expectancy rarely exceeded 30 years. The most common cystic fibrosis mutation (δF508, accounting for about 80% of two million British carriers), is a 3-bp deletion in a transmembrane protein cystic fibrosis transmembrane regulator gene. The next most common three or four mutations account for a further 5% of carriers.. One in 25 white people carries cystic fibrosis. As carriers are unaffected, individuals are often unaware until … ...
Many people with cystic fibrosis are counting on cystic fibrosis transmembrane conductance regulator modulators to improve their overall health. Im learning that they have effects I hadnt counted on.
Cystic fibrosis (CF) lung disease is characterized by chronic bacterial colonization and recurrent infection of the airways. Disruption of the cystic fibrosis transmembrane conductance regulator chloride channels in subjects with CF results in altered fluid and electrolyte transport across the airway epithelium thereby initiating infections.. These infections eventually destroy the lungs and contribute to significant morbidity and mortality in patients with CF. It is well known that antibacterial activity of innate immune mediators such as lysozyme and beta defensins in human airway surface liquid (ASL) is salt-sensitive; an increase in salt concentration inhibits their activity.. Conversely, their activity is increased by low ionic strength. Lowering the ASL salt concentration and increasing the ASL volume might therefore potentiate innate immunity and therefore decrease or prevent airway infections in subjects with CF.. Xylitol, a five-carbon sugar with low transepithelial permeability, which ...
Complex alleles in monogenic disease pose a challenge for clinicians because they are often associated with uncommon diagnostic and clinical features. Here we report on the 30 year course of a basic defect and disease in an individual with cystic fibrosis (CF) who was compound heterozygous for the cystic fibrosis transmembrane conductance regulator (CFTR) mutations R553X1 and the complex allele F508del-R553Q.2. The amino acid substitution R553Q resides within the ABC signature motif of CFTR.3 R553Q has been shown in heterologous model systems to partially correct the defective processing and anomalous ion channel gating of mutant F508del CFTR.4 Hence R553Q has been classified as a disease reverting suppressor mutation. Investigation of the affected subject, however, revealed a more complex manifestation of the basic defect of anomalous epithelial chloride conductance.. The sweat test is still the gold standard to diagnose CF5 whereby elevated sweat chloride concentrations of more than 60 mmol/l ...
Cystic Fibrosis (CF) is a progressive autosomal recessive disorder caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR mutations cause loss or impairment of CFTR-mediated ion transport across epithelial cell membranes. CF affects many organs including the respiratory tract, pancreas, intestine, liver and the male reproductive tract. Liver disease occurs less frequently than pulmonary disease. CFTR is expressed in the bile duct epithelial cells and is responsible for the hydration of biliary secretions.. CF was until recently, thought to be a multi-organ disease. However, there are now recognized non-classical presentations of CF involving a few organs only and now there is well established data on single -organ involvement including Congenital Absence of the Vas Deferens and recurrent pancreatitis.. CF and PSC have several features in common. They both affect intrahepatic bile ducts by inspisated biliary secretions, chronic inflammation and fibrosis. Is ...
Ataluren (PTC 124; PTC Therapeutics),18 currently recognized as an orphan drug by the FDA, is a more appealing therapeutic option for class I CFTR defects. In a mechanism similar to the pleiotropic effects of aminoglycosides, ataluren allows ribosomes to read through the mRNA premature stop codons, resulting in the translation of complete CFTR proteins.19,20 Several phase II and III studies19-21 have evaluated this drugs efficacy and demonstrated improvements in nasal transepithelial potential differences, forced expiratory volume in 1 second (FEV1), and weight gain in both adult and pediatric patient populations.20 Adverse effects were generally mild, with gastrointestinal upset, headache, and dizziness most commonly reported (Table 2). Because of its efficacy in targeting the underlying cause of CF and favorable adverse effect profile, ataluren is considered the more appropriate initial approach compared with aminoglycosides in patients with CF who have class I mutations.10,21 Several phase ...
Background & Aims: Progressive liver disease is a severe complication of cystic fibrosis, a genetic disease characterized by impaired epithelial adenosine 3,5-cyclic monophosphate-dependent secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In the liver, CFTR is expressed in cholangiocytes and regulates the fluid and electrolyte content of the bile. Glibenclamide, a sulfonylurea and a known CFTR inhibitor, paradoxically stimulates cholangiocyte secretion. We studied the molecular mechanisms underlying this effect and whether glibenclamide could restore cholangiocyte secretion in cystic fibrosis. Methods: NRC-1 cells, freshly isolate rat cholangiocytes, isolated rat biliary ducts, and isolated biliary ducts from CFTR-defective mice (Cftr(tm1Unc)) were used to study fluid secretion (by video-optical planimetry), glibenclamide-induced secretion (by high-performance liquid chromatography in cell culture medium), intracellular pH and intracellular Ca2+ ...
Cystic fibrosis (CF) is a common life-shortening, autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel (1). CFTR is expressed in epithelia of multiple organs and its loss causes airway, pancreatic, intestinal, liver, and vas deferens disease. The ΔF508 mutation (also called F508del) is the most common CF-causing mutation, accounting for ~70% of CF alleles; most patients carry at least one ΔF508 allele.. Numerous studies have expressed human CFTR-ΔF508 in vitro and found that its biosynthetic processing is disrupted. The mutant protein is retained in the endoplasmic reticulum (ER) and rapidly degraded (2-4), and as a result, CFTR-ΔF508 fails to reach the apical membrane. However, CFTR-ΔF508 can be induced to traffic to the cell surface by reducing the incubation temperature or adding chemicals that facilitate folding. Once at the membrane, CFTR-ΔF508 retains channel function, although its lifetime ...
Cystic fibrosis (CF) is an autosomal recessive disorder characterized by repeated and destructive lower respiratory infections, resulting in the gradual destruction of the lung tissue.[1]. The cause of CF is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7.[2] The CFTR gene regulates chloride and sodium transport in the epithelial surfaces of the airway, pancreatic and biliary ducts, the gastrointestinal tract, sweat ducts and the vas deferens. Pathogenic mutations either remove or reduce the function of the CFTR gene.[3] This results in the production of sticky mucus build up and blockages that affect mainly the lungs, pancreas and sweat glands.. CF is an inherited condition that affects 1 in 2500 male or female Australian babies. All Australian babies are screened at birth for CF. Blood tests are carried out for the genetic testing of the CFTR gene and sweat tests are carried out to measure the amount of salt in the sweat. There is ...
In order to identify a possible hereditary predisposition to the development of obstructive pulmonary disease of unknown origin, we have looked for the presence of Cystic Fibrosis Transmembrane Regulator (CFTR) gene mutations in unrelated patients with no signs of Cystic Fibrosis (CF). We screened for 70 common mutations, and also for rare mutations by denaturing gradient gel electrophoresis analysis. In this search, different CFTR gene mutations (R75Q, delta F508, R1066C, M1137V and 3667ins4) were found in five out of 16 adult Italian patients with disseminated bronchiectasis, a significant increase over the expected frequency of carriers. Moreover, three rare CFTR gene DNA polymorphisms (G576A, R668C, and 2736 A--,G), not deemed to be the cause of CF, were found in two patients, one of which was a compound heterozygote with R1066C. These results indicate that CFTR gene mutations, and perhaps also DNA polymorphisms, may be involved in the etiopathogenesis of at least some cases of ...
Defects in cystic fibrosis transmembrane conductance regulator (CFTR) can cause cystic fibrosis (CF; MIM:602421), a common generalised disorder in Caucasians affecting the exocrine glands. CF results in an ionic imbalance that impairs clearance of secretions, not only in the lung, but also in the pancreas, gastrointestinal tract and liver. Wide-ranging manifestations of the disease include chronic lung disease, exocrine pancreatic insufficiency, blockage of the terminal ileum, male infertility and salty sweat. The class 3 mutations of CFTR such as G551D strongly decrease the time spent by CFTR in the open state (a gating defect). Results from 2-phase clinical trials using VX-770 (aka Ivacaftor), a CFTR potentiator, showed an increased CFTR channel open probability in G551D patients. Ivacaftor use showed improvements in CFTR and lung function of patients with at least one G551D allele (Accurso et al. 2010, Ramsey et al. 2011, Kapoor et al. 2014). In 2012, the FDA approved Ivacaftor (under the ...
Follow-up testing to identify mutations in individuals with a clinical diagnosis of cystic fibrosis (CF) and a negative targeted mutation analysis for the common mutations. Identification of mutations in individuals with atypical presentations of CF (eg, congenital bilateral absence of the vas deferens or pancreatitis). Identification of mutations in individuals where detection rates by targeted mutation analysis are low or unknown for their ethnic background. Identification of patients who may respond to cystic fibrosis transmembrane conductance regulator (CFTR) potentiator therapy. This is not the preferred genetic test for carrier screening or initial diagnosis. For these situations, order CFB / Cystic Fibrosis Mutation Analysis, 106-Mutation Panel. ...
The expression of cystic fibrosis transmembrane conductance regulator (CFTR) in the thyroid has not been documented to date, although a role for CFTR in the thyroid follicular epithelium is suggested both clinically, by the occurrence of subclinical hypothyroidism in patients with cystic fibrosis (CF), and physiologically, by the presence of low-conductance, adenosine 3,5-cyclic monophosphate-activated Cl channels in the follicular cells. Using reverse transcriptase-polymerase chain reaction with nested primers derived from exons 13 and 14 of the human CF gene, we have now documented the presence of CFTR mRNA in the human thyroid. Western blot analyses using six antibodies directed against different domains of human CFTR showed that a 165-kDa band was present in membrane extracts from bovine and human thyroid. This protein has the predicted size of mature CFTR and was not detected with preimmune serum or preadsorbed antiserum. By immunofluorescence and immunoperoxidase, CFTR was located in the ...
Small-molecule therapies that restore defects in cystic fibrosis transmembrane conductance regulator (CFTR) gating (potentiators) or trafficking (correctors) are being developed for cystic fibrosis (CF) in a mutation-specific fashion. Options for pharmacological correction of CFTR-p.Phe508del (F508del) are being extensively studied but correction of other trafficking mutants that may also benefit from ... read more corrector treatment remains largely unknown.We studied correction of the folding mutants CFTR-p.Phe508del, -p.Ala455Glu (A455E) and -p.Asn1303Lys (N1303K) by VX-809 and 18 other correctors (C1-C18) using a functional CFTR assay in human intestinal CF organoids.Function of both CFTR-p.Phe508del and -p.Ala455Glu was enhanced by a variety of correctors but no residual or corrector-induced activity was associated with CFTR-p.Asn1303Lys. Importantly, VX-809-induced correction was most dominant for CFTR-p.Phe508del, while correction of CFTR-p.Ala455Glu was highest by a subgroup of compounds ...
Day 159 has 30 protein-coding genes (browser view) including CFTR (cystic fibrosis transmembrane conductance regulator.). Like Day 64: (3p22.1-3p21.2): CCR5 Δ32, an HIV resistance mutation, the ΔF508 cystic fibrosis mutation in CFTR is at surprisingly high frequency (1 in 30 Europeans), which has led to speculation that it has been a target of recent evolution - it may provide protection against cholera in people with one copy, despite causing cystic fibrosis when inheriting two copies.. Click here to see all 8386630 letters of Day 159 with the CFTR ΔF508 mutation flashing.. ...
Results Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases-all were classified as small/insufficient or poor quality. ...
Purpose of review New therapeutics have been introduced for cystic fibrosis that modulate cystic fibrosis transmembrane conductance regulator (CFTR) function in a mutation-specific fashion. Despite CFTR genotype-based stratification of treatments, treatment efficacy is variable between study participants suggesting that individual factors further contribute to drug efficacy. Moreover, these treatments are ... read more licensed for a limited amount of CFTR mutations, and study participants with rare mutations that can potentially benefit from available treatments may be missed. New approaches that better support the identification of responders to CFTR modulators are, therefore, needed. Recent findings We, here, review how a patient-oriented research collaboration between basic and clinical scientists and a national cystic fibrosis patient organization led to the development of a CFTR-dependent assay using primary stem cell cultures termed intestinal organoids that can measure the individual ...
Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation ΔF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR
TY - JOUR. T1 - A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. AU - Lee, Ji Hyun. AU - Choi, Ji Ha. AU - Namkung, Wan. AU - Hanrahan, John W.. AU - Chang, Joon. AU - Song, Si Young. AU - Park, Seung Woo. AU - Kim, Dong Soo. AU - Yoon, Joo Heon. AU - Suh, Yousin. AU - Jang, In Jin. AU - Nam, Joo Hyun. AU - Kim, Sung Joon. AU - Cho, Mi Ook. AU - Lee, Jong Eun. AU - Kim, Kyung Hwan. AU - Lee, Min Goo. PY - 2003/9/15. Y1 - 2003/9/15. N2 - Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype ...
Cystic fibrosis (CF) is an autosomal recessive disease that greatly diminishes life span owing to impaired function of the lungs and intestinal epithelia. Although the F508 homozygous mutation in the anion channel protein cystic fibrosis transmembrane conductance regulator (CFTR) is commonly found in CF patients, the mechanisms by which this mutation causes disease are unclear. To investigate this issue in vivo, Ostedgaard et al. generated pigs homozygous for CFTR-F508. Unlike previously established mouse models of CF, CFTR-F508 pigs develop airway and intestinal disease that closely resembles human CF pathology. In vivo studies agreed with previous results carried out in cell culture systems, and showed that the F508 mutation causes CFTR misfolding and degradation, and the failure of the protein to localise at the apical surface of epithelial cells. CFTR-F508 pigs provide a relevant model to further investigate mechanisms of CF pathogenesis and for testing therapies that aim to increase CFTR ...