MS1 VALIDATION OF MODELED 5-YEAR SURVIVAL OUTCOMES AMONG PATIENTS WITH CYSTIC FIBROSIS (CF) TREATED WITH THE CF TRANSMEMBRANE CONDUCTANCE REGULATOR MODULATOR (CFTRM) IVACAFTOR USING US CF FOUNDATION PATIENT REGISTRY (USCFFPR) DATA

The aim of the study was to analyze the data of Ukrainian cystic fibrosis (CF) patients entered to the European Cystic Fibrosis Society Patient Registry (ECFSPR) during 2017–2018 years, and compare with the parameters entered in previous years. Materials and methods. Using the computer program ecfstracker.eu, the clinical, paraclinical and molecular genetic data of CF patients were analyzed and their statistical analysis was performed. Research results. Among 210 CF patients 49 alleles and 68 different genotypes of the CF transmembrane conductance regulator gene were identified. It was found that 57% of CF patients were homozygous for the F508del major mutation, and 31% — heterozygous. The ratio of the proportion of СF patients between children and adults (over 18 years) was 78% and 22%, with an increasing in the proportion of adult patients compared to previous years. Conclusions. The entering data CF patients to the ECFSPR opens new opportunities for a comprehensive analysis of the disease at both on the regional (the center) and on the continental levels. Studying the experience and management of the disease based on the experience of 35 European countries (over 40,000 patients) will not only help to compare the data of Ukrainian patients, but also borrow the best monitoring and treatment schemes from European countries, which help to organize and optimize medical care in Ukraine. No conflict of interest was declared by the authors. Key words: The European Cystic Fibrosis Society Patient Registry, gene, genotype, DNA, molecular genetic research, cystic fibrosis, mutation, CFTR.

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ChemInform Abstract: Combating Cystic Fibrosis: In Search of CF Transmembrane Conductance Regulator (CFTR) Modulators

ChemInform ◽

10.1002/chin.201119257 ◽

2011 ◽

Vol 42 (19) ◽

pp. no-no

Author(s):

Efrat Noy ◽

Hanoch Senderowitz

Keyword(s):

Cystic Fibrosis ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Cf Transmembrane Conductance Regulator ◽

Cftr Modulators

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VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

Molecular Biology of the Cell ◽

10.1091/mbc.e13-05-0240 ◽

2013 ◽

Vol 24 (19) ◽

pp. 3016-3024 ◽

Cited By ~ 158

Author(s):

Hong Yu Ren ◽

Diane E. Grove ◽

Oxana De La Rosa ◽

Scott A. Houck ◽

Pattarawut Sopha ◽

...

Keyword(s):

Cystic Fibrosis ◽

Chloride Transport ◽

Genetic Disorder ◽

Missense Mutations ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Regulator Protein ◽

Folding Defect ◽

Membrane Spanning ◽

Cf Transmembrane Conductance Regulator

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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Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2.

Molecular and Cellular Biology ◽

10.1128/mcb.11.8.3886 ◽

1991 ◽

Vol 11 (8) ◽

pp. 3886-3893 ◽

Cited By ~ 166

Author(s):

R J Gregory ◽

D P Rich ◽

S H Cheng ◽

D W Souza ◽

S Paul ◽

...

Keyword(s):

Cystic Fibrosis ◽

Amino Acid ◽

Functional Activity ◽

Nucleotide Binding ◽

Missense Mutations ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Fluorescence Measurements ◽

Cf Transmembrane Conductance Regulator ◽

Altered Proteins

One feature of the mutations thus far found to be associated with the disease cystic fibrosis (CF) is that many of them are clustered within the first nucleotide-binding domain (NBD) of the CF transmembrane conductance regulator (CFTR). We sought to discover the molecular basis for this clustering by introducing into the two NBDs of CFTR mutations either mimicking amino acid changes associated with CF or altering residues within highly conserved motifs. Synthesis and maturation of the mutant CFTR were studied by transient expression in COS cells. The ability of the altered proteins to generate cyclic AMP-stimulated anion efflux was assessed by using 6-methoxy-N-(sulfopropyl) quinolinium (SPQ) fluorescence measurements in HeLa cells expressing mutated plasmids. The results show that (i) all CF-associated mutants, with one exception, lack functional activity as measured in the SPQ assay, (ii) mutations in NBD1 are more sensitive to the effects of the same amino acid change than are the corresponding mutations in NBD2, (iii) cells transfected with plasmids bearing CF-associated mutations commonly but not exclusively lack mature CFTR, (iv) NBD mutants lacking mature CFTR fail to activate Cl- channels, and (v) the glycosylation of CFTR, per se, is not required for CFTR function. We reason that the structure of NBD1 itself or of the surrounding domains renders it particularly sensitive to mutational changes. As a result, most NBD1 mutants, but only a few NBD2 mutants, fail to mature or lack functional activity. These findings are consistent with the observed uneven distribution of CFTR missense mutations between NBD1 and NBD2 of CF patients.

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Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00030.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. L677-L686 ◽

Cited By ~ 59

Author(s):

R. William Vandivier ◽

Tiffany R. Richens ◽

Sarah A. Horstmann ◽

Aimee M. deCathelineau ◽

Moumita Ghosh ◽

...

Keyword(s):

Cystic Fibrosis ◽

Rho Kinase ◽

Negative Regulator ◽

Apoptotic Cells ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Altered Expression ◽

Proinflammatory Mediators ◽

Downstream Effector ◽

Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target.

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Elevation of hepatic sulphotransferase activities in mice with resistance to cystic fibrosis

Biochemical Journal ◽

10.1042/bj3640115 ◽

2002 ◽

Vol 364 (1) ◽

pp. 115-120 ◽

Cited By ~ 11

Author(s):

Josie L. FALANY ◽

Heather GREER ◽

Timea KOVACS ◽

Eric J. SORSCHER ◽

Charles N. FALANY

Keyword(s):

Cystic Fibrosis ◽

Mouse Liver ◽

Northern Blot Analysis ◽

Transmembrane Conductance Regulator ◽

Male Mice ◽

Transmembrane Conductance ◽

Female Adult ◽

Cf Transmembrane Conductance Regulator ◽

Different Levels

The severity of intestinal disease in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) (-/−) mice has been reported to co-segregate with gene loci which contain the genes for hydroxysteroid sulphotransferase (SULT). Because of the potential involvement of steroid hormones in CF, we investigated levels of steroid SULT activity in the livers of CFTR mice to determine whether the levels of SULT activity correlate with the occurrence or severity of CF. To elucidate the possible role of SULT activity in ameliorating the deleterious effects of CF in CFTR (-/−) mice, we determined the levels of phenol SULT (PST), hydroxysteroid SULT [dehydroepiandrosterone (DHEA)-ST] and oestrogen SULT (EST) activity in control CFTR (+/+), heterozygous CFTR (+/−) and homozygous CFTR (-/−) mice, which survive to adulthood. The level of PST activity was not significantly different between any of the groups of mice, regardless of sex or genotype. Although DHEA-ST activity was significantly higher in female mice than in male mice, there was no difference in DHEA-ST activity that could be correlated with genotype. In contrast with PST and DHEA-ST activities, we found that some male and all female adult CFTR (-/−) mice had elevated, dramatically different levels of EST from both CFTR (+/+) and CFTR (+/−) mice. Results from these SULT activity experiments were confirmed by Northern-blot analysis of mouse-liver RNA. Subsequent studies with preweanling mice revealed no differences in the levels of EST that could be correlated with genotype. Thus this study indicates that EST is elevated significantly in CFTR (-/−) mice which survive to adulthood and provides important biochemical information that EST levels may be protective in CF.

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Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Review for the Otolaryngologist

American Journal of Rhinology and Allergy ◽

10.1177/1945892420912368 ◽

2020 ◽

Vol 34 (4) ◽

pp. 573-580

Author(s):

Saangyoung E. Lee ◽

Zainab Farzal ◽

M.Leigh Anne Daniels ◽

Brian D. Thorp ◽

Adam M. Zanation ◽

...

Keyword(s):

Cystic Fibrosis ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Respiratory Compromise ◽

Basic Understanding ◽

Epithelial Cultures ◽

Cf Transmembrane Conductance Regulator ◽

Cystic Fibrosis Transmembrane ◽

Cftr Modulators ◽

Initial Results

Background Cystic fibrosis (CF) is a genetic disease that may result in multiple systemic disorders and potentially fatal severe respiratory compromise. However, the advent of CF transmembrane conductance regulator (CFTR) modulators has changed the management of CF for patients with select mutations. Although clinical trials have highlighted increased pulmonary function and decreased exacerbations as a result of these novel therapies, their effect on the sinuses has not been well-described. Objective Our objective is to review the CFTR modulators to provide otolaryngologists, physicians who frequently care for patients with CF, a basic understanding of these drugs and their effects on chronic rhinosinusitis (CRS) in patients with CF. Methods The clinically approved and available CFTR modulators and specific indications for their use are reviewed. Additionally, a systematic review of these therapies and effects on CRS in CF was performed. Results Four Food and Drug Administration approved CFTR modulators are available for patients with CF. Current drugs are approved for gating, residual function, or F508del mutations. Multiple reports describe CFTR modulators’ increase in transepithelial ion transport in nasal epithelial cultures; however, clinical studies regarding effects of these modulators on sinonasal health are limited to 5 studies that present new data of the effects of CFTR modulators in CRS. Conclusions CFTR modulators have changed management of CF. Initial studies of these medications demonstrate promising results in CF; however, there is a paucity of literature describing the effect of CFTR modulators on CF-associated CRS, although initial results are encouraging.

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COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code

The Journal of Cell Biology ◽

10.1083/jcb.200401035 ◽

2004 ◽

Vol 167 (1) ◽

pp. 65-74 ◽

Cited By ~ 137

Author(s):

Xiaodong Wang ◽

Jeanne Matteson ◽

Yu An ◽

Bryan Moyer ◽

Jin-San Yoo ◽

...

Keyword(s):

Cystic Fibrosis ◽

Hereditary Disease ◽

Mutant Form ◽

Transmembrane Conductance Regulator ◽

Wild Type ◽

Transmembrane Conductance ◽

Primary Defect ◽

Cf Transmembrane Conductance Regulator ◽

Er Export ◽

Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) ΔF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in ΔF508-expressing patients.

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Cystic fibrosis-related diabetes: an update

QJM ◽

10.1093/qjmed/hcaa256 ◽

2020 ◽

Author(s):

F Frost ◽

M J Walshaw ◽

D Nazareth

Keyword(s):

Cystic Fibrosis ◽

Life Expectancy ◽

Early Mortality ◽

Transmembrane Conductance Regulator ◽

Regulator Gene ◽

Transmembrane Conductance ◽

Common Life ◽

Life Threatening ◽

Underlying Mechanisms ◽

Cf Transmembrane Conductance Regulator

Summary Cystic fibrosis (CF) is the most common life-threatening inherited condition in the Caucasian population, where mutations in the CF transmembrane conductance regulator gene result in a multifactorial syndrome, with pulmonary disease representing the largest contributor to morbidity and mortality. Life expectancy has improved and the recent development of disease-modifying CF transmembrane conductance regulator modulator therapies is likely to further improve survival. However, increasing life expectancy brings new challenges related to the complications of a chronic disease including an increasing prevalence of CF-related diabetes, itself associated with increased morbidity and early mortality. This review provides an update as regards the underlying mechanisms, investigation and management of CF-related diabetes.

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Piperacillin-Induced Immune Hemolytic Anemia in an Adult with Cystic Fibrosis

Case Reports in Medicine ◽

10.1155/2010/161454 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 17

Author(s):

Mahesh Bandara ◽

David B. Seder ◽

George Garratty ◽

Regina M. Leger ◽

Jonathan B. Zuckerman

Keyword(s):

Cystic Fibrosis ◽

Hemolytic Anemia ◽

Rare Complication ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Drug Induced ◽

Immune Hemolytic Anemia ◽

Antiglobulin Test ◽

Cf Transmembrane Conductance Regulator ◽

Positive Direct

We report a case of drug-induced immune hemolytic anemia (DIIHA) in an adult female with cystic fibrosis (CF), complicating routine treatment of a pulmonary exacerbation with intravenous piperacillin-tazobactam. Workup revealed a positive direct antiglobulin test (DAT) due to red blood cell (RBC)-bound IgG and C3 and piperacillin antibodies detectable in the patient's serum. The potential influence of CF transmembrane conductance regulator mutations on the severity of DIIHA is discussed. This report illustrates the importance of early identification of DIIHA, a rare complication of a commonly utilized medication in CF.

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