Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis

Veeze, Henk J.; Sinaasappel, M.; Bijman, J.; Bouquet, J; Jonge, Hugo R. de

doi:10.1016/0016-5085(91)90017-f

Cited by 99 publications

(70 citation statements)

References 22 publications

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“…The degree of CFTR activity in the intestine can be measured using an electrophysiological test: the intestinal current measurement (ICM) [62]. Studies have shown that ICM correlates with CFTR genotype and phenotype [63], and diagnostic sensitivity in difficult CF diagnosis remarkably reaches 100% [64], making this tool also a potentially useful CF biomarker.…”

Section: Cftr Correctorsmentioning

confidence: 99%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

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Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

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Section: Cftr Correctorsmentioning

confidence: 99%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

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“…The muscle layers were stripped off by blunt dissection, and the mucosa was mounted in an Ussing chamber (0.3-cm 2 area exposed) for measurements of short-circuit current (I sc ) across the tissue as described (24). Dose-response curves were obtained by cumulative additions of agonists or antagonists, and subsequent measurements of the plateau phase of the I SC reached 10 -20 min after each addition.…”

Section: Preparation Of Various Cgk Ii-containing Membranes and Purifmentioning

confidence: 99%

Endogenous Type II cGMP-dependent Protein Kinase Exists as a Dimer in Membranes and Can Be Functionally Distinguished from the Type I Isoforms

Vaandrager¹,

Edixhoven²,

Bot³

et al. 1997

Journal of Biological Chemistry

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In mammalian tissues two types of cGMP-dependent protein kinase (cGK) have been identified. In contrast to the dimeric cGK I, cGK II purified from pig intestine was shown previously to behave as a monomer. However, recombinant rat cGK II was found to have hydrodynamic parameters indicative of a homodimer. Chemical cross-linking studies showed that pig cGK II in intestinal membranes has a dimeric structure as well. However, after purification, cGK II was found to be partly proteolyzed into C-terminal monomeric fragments. Phosphorylation studies in rat intestinal brush borders revealed that the potency of cGMP analogs to stimulate or inhibit native cGK II in vitro (i.e. 8-(4-chlorophenylthio)-cGMP > cGMP > ␤-phenyl-1,N 2 -etheno-8-bromocGMP > ␤-phenyl-1,N 2 -etheno-cGMP and R p -8-(4-chlorophenylthio)-cGMPs > R p -␤-phenyl-1,N 2 -etheno-8-bromocGMPs, respectively) correlated well with their potency to stimulate or inhibit cGK II-mediated Cl ؊ secretion across intestinal epithelium but differed strikingly from their potency to affect cGK I activity. These data show that the N terminus of cGK II is involved in dimerization and that endogenous cGK II displays a distinct activation/inhibition profile with respect to cGMP analogs, which permits a pharmacological dissection between cGK II-and cGK I-mediated physiological processes.

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“…Early immunofluorescence studies described localization of WT but not ⌬F508 CFTR to the apical PM of the sweat duct (Cohn et al, 1991;Kartner et al, 1992) and airway submucosal glands (Engelhardt et al, 1992;Puchelle et al, 1992). Functional studies also failed to detect a cAMP-dependent Cl Ϫ secretion in native CF airway and intestinal epithelia (Boucher et al, 1989;Veeze et al, 1991;Mall et al, 2004). However, the concept that the pathophysiology of ⌬F508 CFTR in native epithelia reflects predominantly defective processing and protein mislocalization has been challenged.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

Kreda

Mall

Mengos

et al. 2005

MBoC

233

210

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Previous studies in native tissues have produced conflicting data on the localization and metabolic fate of WT and ⌬F508 cystic fibrosis transmembrane regulator (CFTR) in the lung. Combining immunocytochemical and biochemical studies utilizing new high-affinity CFTR mAbs with ion transport assays, we examined both 1) the cell type and region specific expression of CFTR in normal airways and 2) the metabolic fate of ⌬F508 CFTR and associated ERM proteins in the cystic fibrosis lung. Studies of lungs from a large number of normal subjects revealed that WT CFTR protein localized to the apical membrane of ciliated cells within the superficial epithelium and gland ducts. In contrast, other cell types in the superficial, gland acinar, and alveolar epithelia expressed little WT CFTR protein. No ⌬F508 CFTR mature protein or function could be detected in airway specimens freshly excised from a large number of ⌬F508 homozygous subjects, despite an intact ERM complex. In sum, our data demonstrate that WT CFTR is predominantly expressed in ciliated cells, and ⌬F508 CFTR pathogenesis in native tissues, like heterologous cells, reflects loss of normal protein processing.

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Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis

Cited by 99 publications

References 22 publications

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Endogenous Type II cGMP-dependent Protein Kinase Exists as a Dimer in Membranes and Can Be Functionally Distinguished from the Type I Isoforms

Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

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