Cystic Fibrosis
New England Journal of MedicinePublished 11 May 2005
Steven M. Rowe, Stacey Miller, Eric J. Sorscher
Citations1,378
SJR quartileQ1
SJR score19.08
SNIP13.47
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TL;DR
From the Gregory Fleming James Cystic Fibrosis Research Center (S.M.R., S.J.S.), University of Alabama at Birmingham, Birmingham.
Abstract
This review of the genetics and molecular mechanisms of cystic fibrosis emphasizes recent progress and recounts the historical background that made these new advances possible.
Keywords
MedicineNursing
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7,425 Citations1989John R. Riordan, Johanna M. Rommens +12 more
A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
ScienceIdentification of the Cystic Fibrosis Gene: Genetic Analysis
4,129 Citations1989Bat-Sheva Kerem, Johanna M. Rommens +6 more
Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations.
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3,241 Citations1989Johanna M. Rommens, Michael C. Iannuzzi +13 more
Several transcribed sequences and conserved segments were identified in this cloned region and one corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.
American Journal of Respiratory and Critical Care MedicinePathophysiology and Management of Pulmonary Infections in Cystic Fibrosis
1,630 Citations2003Ronald L. Gibson, Jane L. Burns +1 more
This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis and potential future therapies.
Annual Review of BiochemistryMammalian ABC Transporters in Health and Disease
1,575 Citations2002Piet Borst, R. Oude Elferink
This work focuses on three topics: ABC transporters transporting drugs (xenotoxins) and drug conjugates, and a rapidly increasing number of ABC Transporters found to play a role in lipid transport.
CellMolecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis
1,459 Citations1993Michael J. Welsh, Alan E. Smith
Cystic fibrosis is a regulated Cl- channel, for which structure-function relationships have begun to be established, and insight into the functions of individual domains has come from a number of studies.
NatureGene expression in Pseudomonas aeruginosa biofilms
1,174 Citations2001Marvin Whiteley, M. Gita Bangera +5 more
DNA microarrays show that gene expression in biofilm cells is similar to that in free-living cells but there are a small number of significant differences, which points to mechanisms of biofilm resistance to antibiotics.
CellCystic Fibrosis Airway Epithelia Fail to Kill Bacteria Because of Abnormal Airway Surface Fluid
1,030 Citations1996Jeffrey J. Smith, Sue M. Travis +2 more
It is shown that common CF pathogens were killed when added to the apical surface of normal airway epithelia, showing how the loss of CFTR Cl- channels may lead to lung disease and suggest new approaches to therapy.
New England Journal of MedicineMutations in the Cystic Fibrosis Gene in Patients with Congenital Absence of the Vas Deferens
967 Citations1995Miguel Chillón, Teresa Casals +11 more
The combination of the 5T allele in one copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most common cause of CBAVD.
New England Journal of MedicineMutations of the Cystic Fibrosis Gene in Patients with Chronic Pancreatitis
963 Citations1998NICHOLAS H. SHARER, Martin Schwarz +5 more
It is hypothesized that mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more common than expected among patients with chronic pancreatitis.
CellPurification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR)
946 Citations1992Christine E. Bear, Canhui Li +5 more
New England Journal of MedicineRelation between Mutations of the Cystic Fibrosis Gene and Idiopathic Pancreatitis
925 Citations1998Jonathan Cohn, Kenneth J. Friedman +4 more
There was a strong association between mutations in the CFTR gene and pancreatitis, and the abnormal CFTR genotypes in these patients with pancreatitis resemble those associated with male infertility.
Nature MedicineIncreased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice
899 Citations2004Marcus Mall, Barbara R. Grubb +3 more
It is concluded that increasing airway Na+ absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.
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884 Citations2003Félix Ratjen, Gerd Döring
Advances in understanding and treatment of cystic fibrosis are summarized, focusing on pulmonary disease, which accounts for most morbidity and deaths.
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706 Citations1990Devra P. Rich, Matthew P. Anderson +8 more
Exposure of CFTR to cultured cystic fibrosis airway epithelial cells corrected the Cl− channel defect, demonstrating a causal relationship between mutations in the CFTR gene and defective Cl− transport which is the hallmark of the disease.
Nature GeneticsSubmucosal glands are the predominant site of CFTR expression in the human bronchus
649 Citations1992John F. Engelhardt, James R. Yankaskas +6 more
The data suggest mechanisms whereby defects in CFTR expression could lead to abnormal production of mucus in human lung, particularly in non–CF individuals.
Annual Review of GeneticsCYSTIC FIBROSIS: GENOTYPIC AND PHENOTYPIC VARIATIONS
616 Citations1995Julian Zielenski, Lap Chee Tsui
An unexpected finding is the documentation of CFTR mutations in patients with atypical CF disease presentations, including congenital absence of vas deferens and several pulmonary diseases, suggesting that the implication ofCFTR mutation is more profound than CF alone.
New England Journal of MedicineIncreased Bioelectric Potential Difference across Respiratory Epithelia in Cystic Fibrosis
582 Citations1981Michael R. Knowles, John T. Gatzy +1 more
The increased respiratory-epithelial potential differences appear to be a specific abnormality in homozygotes for cystic fibrosis, which suggests that absorption of excess salt and perhaps liquid from respiratory epithelial surfaces contributes to the pathogenesis of lung disease in cysts fibrosis.
CHEST JournalCystic Fibrosis Adult Care
577 Citations2004James R. Yankaskas, Bruce C. Marshall +3 more
This work aims to provide a standard of care for cystic fibrosis patients with at-risk children in the United States using a simple, scalable, and scalable approach that reduces uncertainty and uncertainty about the severity of the disease.
ScienceCurcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects
561 Citations2004Marie E. Egan, Marilyn Pearson +8 more
Curcumin treatment may be able to correct defects associated with the homozygous expression of ΔF508 CFTR, which results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation.
New England Journal of MedicineGentamicin-Induced Correction of CFTR Function in Patients with Cystic Fibrosis and<i>CFTR</i>Stop Mutations
487 Citations2003Michael Wilschanski, Yaacov Yahav +10 more
In patients with cystic fibrosis who have premature stop codons, gentamicin can cause translational "read through," resulting in the expression of full-length CFTR protein at the apical cell membrane, and thus can correct the typical electrophysiological abnormalities caused by CFTR dysfunction.
Journal of Biological ChemistryAn Apical PDZ Protein Anchors the Cystic Fibrosis Transmembrane Conductance Regulator to the Cytoskeleton
466 Citations1998Douglas B. Short, Kevin W. Trotter +6 more
Through formation of a complex, the interaction between CFTR and EBP50 may influence the stability and/or regulation of CFTR Cl−channel function in the cell membrane and provides a potential mechanism through which CFTR can affect the activity of other apical membrane proteins.
Journal of Clinical InvestigationAssociation of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis
433 Citations1999Peter Garred, Tacjana Pressler +6 more
Presence of MBL variant alleles is associated with poor prognosis and early death in patients with CF and the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes.
The EMBO JournalStructure of nucleotide‐binding domain 1 of the cystic fibrosis transmembrane conductance regulator
406 Citations2003H.A. Lewis, Sean G. Buchanan +22 more
Crystal structures for mouse NBD1 in unliganded, ADP‐ and ATP‐bound states, with and without phosphorylation are determined, consistent with a CFTR mechanism, whereby channel gating occurs through ATP binding in an N BD1–NBD2 nucleotide sandwich that forms upon displacement of NBD 1 regulatory segments.
New England Journal of MedicineAssociation of Cystic Fibrosis with Abnormalities in Fatty Acid Metabolism
394 Citations2004Steven D. Freedman, Paola G. Blanco +10 more
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391 Citations1986Michael J. Welsh, Carole M. Liedtke
NaturePhosphorylation fails to activate chloride channels from cystic fibrosis airway cells
337 Citations1987Robert Schoumacher, Richard L. Shoemaker +4 more
The failure of the C subunit to activate the Cl− channels of CF membranes indicates that the block in their cAMP-mediated activation lies distal to induction of camp-dependent protein kinase activity and focuses attention on the Cl − channel and its membrane-associated regulatory proteins as the probable site of the CF defect.
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275 Citations1983Michael Knowles, J. T. Gatzy +1 more
Three abnormalities (decreased Cl- permeability, raised PD, greater amiloride efficacy) have been identified in CF respiratory epithelia Whereas "excessive" active Na+ transport can account for these abnormalities and the dessication of airway surface liquid, it is possible that a lower lumenal cell membrane Cl- porousness and inhibition of a potential path of Cl- secretion can also explain the observations.
American Journal of Respiratory Cell and Molecular BiologyToll-Like Receptors in Normal and Cystic Fibrosis Airway Epithelial Cells
257 Citations2003Amanda B. Muir, Grace Soong +5 more
Increased availability of TLR2 at the apical surfaces of CF epithelial cells is consistent with the increased proinflammatory responses seen in CF airways and suggests a selective participation of TLRs in the airway mucosa.
Annals of NeurologyGentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations
255 Citations2001Kathryn R. Wagner, Sherifa A. Hamed +6 more
In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype, and full‐length dyStrophin was not detected in pre‐ and post‐treatment muscle biopsies.
American Journal of Respiratory and Critical Care MedicineEvidence that Systemic Gentamicin Suppresses Premature Stop Mutations in Patients with Cystic Fibrosis
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Gentamicin treatment can suppress premature stop mutations in airway cells from patients with CF, and produce small increases in CFTR Cl(-) conductance (as measured by the nasal PD) in vivo.
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229 Citations2003A. S. Verkman, Yuanlin Song +1 more
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214 Citations2001Luis J. V. Galietta, Sujatha Jayaraman +1 more
A rapid, quantitative screening procedure for analysis of CFTR-mediated halide transport in cells with the use of a conventional fluorescence plate reader and cell lines is developed to facilitate the screening of novel CFTR activators and the characterization of alternative Cl(-) channels and transporters.
Journal of Biological ChemistryNovel CFTR Chloride Channel Activators Identified by Screening of Combinatorial Libraries Based on Flavone and Benzoquinolizinium Lead Compounds
213 Citations2001Luis J. V. Galietta, Mark F. Springsteel +7 more
The results establish an efficient screening procedure to identify CFTR activators and inhibitors and have identified 7,8-benzoflavones and pyrazolo derivatives as novel classes of CFTR Activators.
ScienceAn Apical-Membrane Chloride Channel in Human Tracheal Epithelium
207 Citations1986Michael J. Welsh
Results suggest that an anion-selective channel that was not strongly voltage-gated or regulated by calcium in cell-free patches is responsible for the apical chloride conductance in airway epithelia.
Journal of Biological ChemistryC-terminal Truncations Destabilize the Cystic Fibrosis Transmembrane Conductance Regulator without Impairing Its Biogenesis
205 Citations1999Martin Haardt, Mohamed Benharouga +3 more
It is suggested that the C terminus has a central role in maintaining the metabolic stability of the complex-glycosylated CFTR following its exit from the ER and provide a plausible explanation for the severe phenotype of CF patients harboring C-terminal truncations.
Proceedings of the National Academy of SciencesSubmucosal gland secretions in airways from cystic fibrosis patients have normal [Na <sup>+</sup> ] and pH but elevated viscosity
196 Citations2001Sujatha Jayaraman, Nam Soo Joo +3 more
These results represent the first direct measurements of ionic composition and viscosity in uncontaminated human gland secretions and indicate similar [Na+], [Cl−], and pH to that in the airway surface liquid.
New England Journal of MedicineA Cystic Fibrosis Mutation Associated with Mild Lung Disease
176 Citations1995K. H. Gan, Henk J. Veeze +8 more
Because mortality in this disease depends primarily on the progression of pulmonary disease, patients with the A455E mutation have a better prognosis than patients who are homozygous for the delta F508 mutation.
Journal of Biological ChemistryHigh-affinity Activators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Conductance Identified by High-throughput Screening
175 Citations2002Tonghui Ma, L. Vetrivel +5 more
The new activators identified here may be useful in defining molecular mechanisms of CFTR activation and as lead compounds in CF drug development.
Human Molecular GeneticsGentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation
163 Citations2001Kim M. Keeling
It is found that gentamicin treatment reduced GAG accumulation in Hurler cells to a normal level, and the suppression of premature stop mutations may provide an effective treatment for Hurler syndrome patients with premature start mutations in the IDUA gene.
Journal of Molecular MedicineClinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system
143 Citations2002Kim M. Keeling, David M. Bedwell
Amikacin represents an alternative to gentamicin for suppression therapy in certain contexts, thus providing a means of optimizing the efficacy of aminoglycoside-mediated suppression of premature stop mutations.
The Journal of PediatricsInduced sputum inflammatory measures correlate with lung function in children with cystic fibrosis
135 Citations2002Scott D. Sagel, Marci K. Sontag +4 more
It is concluded that measures of inflammation in induced sputum correlate with FEV(1) in clinically stable children with CF with normal to mildly abnormal lung function and that they may be useful as surrogate outcome measures in clinical trials.
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122 Citations1996K.N. Olivier, William D. Bennett +5 more
It is concluded that aerosolized UTP +/- amiloride clearly enhances mucociliary clearance without acute adverse effects in normal adults, and may have therapeutic potential to enhance airways clearance in diseases characterized by retained airways secretions.
American Journal of Physiology-Cell PhysiologyDrug discovery in academia
122 Citations2004A. S. Verkman
The discovery of small molecule inhibitors and activators of the cystic fibrosis transmembrane conductance regulator is presented as an example of an academic drug discovery program that has yielded new compounds for physiology research and clinical development.
Journal of Biological ChemistryAbsent Secretion to Vasoactive Intestinal Peptide in Cystic Fibrosis Airway Glands
121 Citations2002Nam Soo Joo, Toshiya Irokawa +4 more
A major defect in CF glands is discovered by in situ optical monitoring of secretions from single human airway glands and the complete absence of secretion to agents that elevate [cAMP] i suggests that altered secretion of gland mucus could contribute to CF lung disease.
American Journal of Physiology-Cell PhysiologyMissing Cl conductance in cystic fibrosis
113 Citations1986Paul Quinton
The Cl impermeability that is characteristic of the CF tissue is due to the almost complete absence of an electrodiffusive shunt for Cl across this epithelium, while the remaining conductance components are probably not altered.
American Journal of Respiratory Cell and Molecular BiologyLung Inflammation as a Therapeutic Target in Cystic Fibrosis
110 Citations2004David R. Koehler, Gregory P. Downey +3 more
The mechanisms responsible for inflammation in the CF lung are examined, potential therapeutic strategies targeting inflammation are discussed, and potential therapeutic strategy targeting inflammation is discussed.
Journal of Biological ChemistryTranscriptional Adaptation to Cystic Fibrosis Transmembrane Conductance Regulator Deficiency
86 Citations2003Yan Xu, Jean C. Clark +5 more
Of RNAs whose expression was consistently altered by the absence of CFTR, functional classes of genes influencing gene transcription, inflammation, intracellular trafficking, signal transduction, and ion transport were identified.
American Journal of Diseases of ChildrenFIBROSIS OF THE PANCREAS IN INFANTS AND CHILDREN
85 Citations1949C. U. Lowe
A statistical analysis of the data which have been obtained from a study of 134 patients with fibrosis of the pancreas who were seen at the Infants' and Children's Hospital in Boston during the past ten years is presented.
Journal of Biological ChemistryMucus Secretion from Single Submucosal Glands of Pig
80 Citations2002Nam Soo Joo, Yamil Sáenz +3 more
The strong secretory response to vasoactive intestinal peptide, the acidity of [cAMP] i -stimulated mucus, and its inhibition by bumetanide were unexpected.
Advanced Drug Delivery ReviewsPharmacological approaches for the discovery and development of new anti-inflammatory agents for the treatment of cystic fibrosis
72 Citations2002Michael W. Konstan, Pamela B. Davis
Treating the inflammatory response is important, for the data from the ibuprofen study show that the effects of anti-inflammatory therapy are additive or even synergistic with intensive conventional therapy and alter the rate of decline of pulmonary function, and therefore benefits for survival of patients with CF are to be expected.
Pediatric PulmonologyCombination anti‐inflammatory and antiviral therapy of influenza in a cotton rat model
57 Citations2003Martin G. Ottolini, Jorge C. G. Blanco +4 more
Tissue damage during influenza infection may be greatly reduced by combination antiviral and anti‐inflammatory therapy, which was observed in all combinations where 4 or 16 mg/kg of triamcinolone were used.
Assay and Drug Development TechnologiesFlux Assays in High Throughput Screening of Ion Channels in Drug Discovery
54 Citations2003Sikander Gill, Raj Gill +6 more
The nonradiolabeled rubidium-based flux assay coupled with the ion channel reader (ICR) technology has become very successful in ion channel activity analysis and is emerging as a popular technique in modern drug discovery.
American Journal of Respiratory Cell and Molecular Biologyα1-Antitrypsin Deficiency Alleles in Cystic Fibrosis Lung Disease
50 Citations2003Despina D. Frangolias, Jian Ruan +12 more
It is found that the Z, S, and G1237→A polymorphisms of the α1-AT gene are one of the few antiproteases capable of inactivating neutrophil elastase and the CFTR genotype does not explain the heterogeneity observed in CF pulmonary disease severity.
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48 Citations2002Scott D. Sagel, Frank J. Accurso
The current state of knowledge regarding individual cytokines and CF lung disease is reviewed, with an eye towards the possibility that cytokines may be used as outcome measures in clinical trials in CF.
MicrobiologyStatic growth of mucoid Pseudomonas aeruginosa selects for non-mucoid variants that have acquired flagellum-dependent motility a aPresent address: Division of Science and Mathematics, University of Minnesota-Morris, Morris, MN 56267, USA.
48 Citations2002Timna J.O. Wyckoff, Brittany Thomas +2 more
It is suggested that the first effect of static growth is to induce motility as an adaptive measure in the presence of wild-type algT, which may afford P. aeruginosa the ability to swim towards areas of higher oxygen concentrations.
Kidney InternationalPharmacologic restoration of αδF508 CFTR-mediated chloride current
39 Citations2000Pamela L. Zeitlin
The hypothesis of this discussion is that the short chain fatty acids, butyrate and 4-phenylbutyrate, up-regulate mature CFTR at the plasma membrane and evidence that these compounds regulate CFTR production and maturation in part through effects on molecular chaperones in CF cells in culture is discussed.