Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function

Goor, Fredrick Van; Yu, Hang; Burton, Bill; Hoffman, Beth J.

doi:10.1016/j.jcf.2013.06.008

Cited by 302 publications

(382 citation statements)

References 26 publications

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“…32 In Fisher rat thyroid cells G551D showed 1% of wild-type function, and human bronchial epithelial cells generated from G551D/F508del lung explants expressed 5% wild-type CFTR function. 24 Our results suggest that, in contrast to classes I and II, class III CFTR mutations confer sufficient chloride channel function to maintain early intestinal fluid homeostasis and thus eliminate the risk for MI in patients with CF.…”

Section: Discussionmentioning

confidence: 64%

“…While non-CFTR modifier genes as well as environmental factors largely influence the development and progression of lung disease and nutritional decline, [33][34][35][36] we demonstrate that the severity of the underlying CFTR genotype 24 for the major and missense cystic fibrosis-causing variants for which patient group size was ≥10 in at least the US group. itself plays a role in predisposing patients to an overall better or worse clinical outcome measured as lung function and nutritional status.…”

Section: Discussionmentioning

confidence: 80%

“…The calculated MIP score is well in agreement with previously published information about the functional expression of different CFTR mutations. VanGoor et al 24 recently compared the magnitude of mRNA expression levels, the levels of mature CFTR protein, as well as the chloride channel activity of a large number of missense variants using a Fisher rat thyroid cell expression system. Comparing findings with ours, we observe that generally, the MIP score correlates with the CFTR functional levels (P = 0.009; Table 2).…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Dupuis

Keenan

Ooi

et al. 2016

Genetics in Medicine

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Rationale: Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype-phenotype correlation for severe mutations.Method: MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). Results:The prevalence of MI varied among the different registries (13-21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying "severe" CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04).Conclusions: MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Dupuis

Keenan

Ooi

et al. 2016

Genetics in Medicine

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“…The CFTR potentiator creates opportunities for personalised medicine for CF However, because the G551D mutation affects only ,4% of CF patients worldwide, considerable challenges remain that need to be overcome before a larger group of patients can benefit from these novel CFTR modulator therapies. In this context, recent in vitro studies demonstrated that ivacaftor can improve the open probability and, thus, potentiate other non-G551D gating mutations, as well as other rare CFTR mutations that cause mild defects in processing and/or conductance [74,75]. These results indicate that ivacaftor may be more broadly acting and beneficial for a larger group of CF patients that carry CFTR mutations with residual function, including pancreatic-sufficient patients.…”

Section: Emerging Novel Therapies To Rescue Mutant Cftr: Breakthroughmentioning

confidence: 94%

CFTR: cystic fibrosis and beyond

2014

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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 DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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“…While both drugs are assumed to directly bind to mutant and wild-type CFTR, lumacaftor has been shown to stabilize the NBD1/MSDs interface in CFTR variants both in the ER and the PM [108,109]. In contrast, ivacaftor can stimulate the gating of several missense mutations with impaired channel activation upon PKA-mediated phosphorylation [110]. Thus, lumacaftor and ivacaftor may have the potential to revert the conformational and functional defects, respectively, of the ethanol-induced dysfunctional CFTR, a scenario that has to be evaluated experimentally in the future.…”

mentioning

confidence: 99%

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

Hegyi

2016

Pancreatology

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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking or bile acids strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.Corresponding author: Prof. Dr. Peter Hegyi, Doctor of the Hungarian Academy of Sciences, First Department of Medicine, University of Szeged, Koranyi fsr. 8-10, SZEGED, H6720, Hungary, TEL: +3662545200, FAX: +3662545185, MOBILE: +36703751031, hegyi.peter@med.u-szeged.hu. Conflict of interest statement: the authors have no conflict of interest to declare HHS Public Access I. Basics of CFTR a. Biosynthesis and degradationThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cyclic AMP (cAMP)-regulated chloride (Cl − )/bicarbonate (HCO 3 − ) channel, expressed in the apical plasma membrane (PM) of secretory epithelia in the airways, pancreas, intestine, reproductive organs and exocrine glands [1]. CFTR consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2) (Figure 1). The two halves are connected by the R domain [2]. The NBDs contain conserved ATP-binding sequences: Walker A and B motifs, classifying CFTR as a member of the ATP-binding cassette (ABC) transporter family. Structural, biochemical and functional evidence suggest that the two NBD domains interact and the ATP-binding site of one NBD is complemented by the ABC signature motif of the other [2].While NBD1 folds largely co-translationally, the native fold of NBD2 as well as CFTR are attained post-translationally [3]. Assembly of MSD1, NBD1, R domain and MSD2 is necessary and sufficient to form the minimal folding unit of CFTR [4]. These and other observations support the cooperative domain folding model and ensure the dynamic conformational coupling between the cytosolic NBDs and the pore-forming MSDs in the native molecule and provide a structural explanation for the cooperative domain unfolding, caused by cystic fibrosis (CF) mutations [4].Despite interactions with several cytosolic and endoplasmic reticulum (ER) chapero...

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Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function

Abstract: These in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.

Cited by 302 publications

References 26 publications

Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

CFTR: cystic fibrosis and beyond

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

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