oalib
Search Results: 1 - 10 of 100 matches for " "
All listed articles are free for downloading (OA Articles)
Page 1 /100
Display every page Item
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.
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.
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.
'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations
Peadar G Noone, Michael R Knowles
Respiratory Research , 2001, DOI: 10.1186/rr82
Abstract: Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations on both CFTR alleles, resulting in abnormal sweat electrolytes, sino-pulmonary disease, male infertility, and pancreatic exocrine insufficiency in 95% of patients [1,2]. In its classic form, the disease is easily diagnosed early in life, through a combination of clinical evaluation and laboratory testing (including sweat testing, and CFTR mutation analysis) [3]. Depending on the ethnic background of the populations tested, common genetic mutations are identified in the majority of cases of CF. In the USA, two-thirds of patients carry at least one copy of the ΔF508 mutation, with approximately 50% of CF patients being homozygous for this mutation [4].A wide spectrum of molecular abnormalities may occur in the CFTR gene, and uncommon mutations that result in partial (residual) CFTR function may be associated with nonclassic presentations of disease. Overall, 7% of CF patients are not diagnosed until age 10 years, with a proportion not diagnosed until after age 15 years; some of these patients present a considerable challenge in establishing a diagnosis of CF. Moreover, the phenotype in these patients may vary widely [5,6]. The focus of the present review is on nonclassic phenotypes associated with mutations in the CFTR gene, which may manifest as male infertility (congenital bilateral absence of the vas deferens [CBAVD]), mild pulmonary disease and idiopathic chronic pancreatitis (ICP). These phenotypes are included within the definition of 'atypical CF'.CFTR is a transmembrane spanning protein with multiple activities that are related to normal epithelial cell function [2]. Mutations in CFTR result in abnormalities in epithelial ion and water transport, which are associated with derangements in airway mucociliary clearance and other cellular functions related to normal cell biology [7]. Depending on the molecular abnormality, the defect in CFTR may be the equivalent of that associated wit
The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse
J Craig Cohen, Lennart KA Lundblad, Jason HT Bates, Michael Levitzky, Janet E Larson
BMC Genetics , 2004, DOI: 10.1186/1471-2156-5-21
Abstract: Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations.In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung.Cystic fibrosis (CF) is a progressive disease primarily affecting the intestines, lungs, and pancreas. The gene responsible for CF was identified in 1989 [1] as coding for the cystic fibrosis transmembrane conductance regulator (cftr), a membrane chloride channel. CF is one of the most common autosomal recessive diseases in Caucasians with a carrier rate of 3–4% [2], and is characterized by recurrent infection and chronic inflammation. Recently it was found that infants with CF demonstrate changes in forced expiratory volume in 1 second (FEV1), functional residual capacity (FRC), and other parameters of lung function prior to the onset of recurrent infection [3-5].Soon after the CF gene was discovered, a knockout mouse was developed. This mouse demonstrates subtle changes in epithelial cell phenotype, including alterations in secretory glycoconjugates and changes in secretory vesicles [6]. Monocytic infiltrates and altered
The Mitochondrial Complex I Activity Is Reduced in Cells with Impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Function  [PDF]
Angel G. Valdivieso, Mariángeles Clauzure, María C. Marín, Guillermo L. Taminelli, María M. Massip Copiz, Francisco Sánchez, Gustavo Schulman, María L. Teiber, Tomás A. Santa-Coloma
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048059
Abstract: Cystic fibrosis (CF) is a frequent and lethal autosomal recessive disease. It results from different possible mutations in the CFTR gene, which encodes the CFTR chloride channel. We have previously studied the differential expression of genes in CF and CF corrected cell lines, and found a reduced expression of MTND4 in CF cells. MTND4 is a mitochondrial gene encoding the MTND4 subunit of the mitochondrial Complex I (mCx-I). Since this subunit is essential for the assembly and activity of mCx-I, we have now studied whether the activity of this complex was also affected in CF cells. By using Blue Native-PAGE, the in-gel activity (IGA) of the mCx-I was found reduced in CFDE and IB3-1 cells (CF cell lines) compared with CFDE/6RepCFTR and S9 cells, respectively (CFDE and IB3-1 cells ectopically expressing wild-type CFTR). Moreover, colon carcinoma T84 and Caco-2 cells, which express wt-CFTR, either treated with CFTR inhibitors (glibenclamide, CFTR(inh)-172 or GlyH101) or transfected with a CFTR-specific shRNAi, showed a significant reduction on the IGA of mCx-I. The reduction of the mCx-I activity caused by CFTR inhibition under physiological or pathological conditions may have a profound impact on mitochondrial functions of CF and non-CF cells.
Analysis of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene in patients with obstructive azoospermia
Bernardino, Andrea L.F.;Lima, Cintia E.;Zatz, Mayana;
Genetics and Molecular Biology , 2003, DOI: 10.1590/S1415-47572003000100001
Abstract: congenital bilateral absence of the vas deferens (cbavd) accounts for 1%-2% of sterility in men. a high incidence of mutations, as well as the involvement of the 5t variant of the t tract length in intron 8 of the cystic fibrosis conductance regulator (cftr) gene, have been previously described in males with cbavd. herein we report the screening for mutations and for the 5t variant of the cftr gene in 17 patients with cbavd and three others with non-cabvd obstructive azoospermia. in the cbavd group, three patients (15%) were compound heterozygotes for mutations, and five patients (25%) had a mutation in one allele and the 5t variant in the other; the 5t variant was also present in two other patients, one of them being homozygous. the most frequent mutation was df508, present on five chromosomes (12.5%). a novel missense mutation (a399d) was detected in a japanese cbvad patient. our results yield further evidence for a strong association between male obstructive azoospermia caused by cbavd and mutation/5t variant in the cftr gene. the search for cftr mutations in such patients is thus recommended for genetic counseling of couples who undergo assisted fertilization due to cbavd.
Analysis of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene in patients with obstructive azoospermia  [cached]
Bernardino Andrea L.F.,Lima Cintia E.,Zatz Mayana
Genetics and Molecular Biology , 2003,
Abstract: Congenital bilateral absence of the vas deferens (CBAVD) accounts for 1%-2% of sterility in men. A high incidence of mutations, as well as the involvement of the 5T variant of the T tract length in intron 8 of the cystic fibrosis conductance regulator (CFTR) gene, have been previously described in males with CBAVD. Herein we report the screening for mutations and for the 5T variant of the CFTR gene in 17 patients with CBAVD and three others with non-CABVD obstructive azoospermia. In the CBAVD group, three patients (15%) were compound heterozygotes for mutations, and five patients (25%) had a mutation in one allele and the 5T variant in the other; the 5T variant was also present in two other patients, one of them being homozygous. The most frequent mutation was DF508, present on five chromosomes (12.5%). A novel missense mutation (A399D) was detected in a Japanese CBVAD patient. Our results yield further evidence for a strong association between male obstructive azoospermia caused by CBAVD and mutation/5T variant in the CFTR gene. The search for CFTR mutations in such patients is thus recommended for genetic counseling of couples who undergo assisted fertilization due to CBAVD.
Osteoblast CFTR Inactivation Reduces Differentiation and Osteoprotegerin Expression in a Mouse Model of Cystic Fibrosis-Related Bone Disease  [PDF]
Michael S. Stalvey, Katrina L. Clines, Viktoria Havasi, Christopher R. McKibbin, Lauren K. Dunn, W. Joon Chung, Gregory A. Clines
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080098
Abstract: Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF). CF-related bone disease (CFBD) is characterized by uncoupled bone turnover—impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR), the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr?/?) mouse model. In the murine calvarial organ culture assay, Cftr?/? calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+) littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr?/? compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl) mRNA was detected, significantly less osteoprotegerin (Opg) was expressed in Cftr?/? compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr?/? murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt signaling was defective in Cftr?/? murine calvarial osteoblasts. These results support that genetic inactivation of CFTR in osteoblasts contributes to low bone mass and that targeting osteoblasts may represent an effective strategy to treat CFBD.
Page 1 /100
Display every page Item


Home
Copyright © 2008-2017 Open Access Library. All rights reserved.