Maintaining Low Ca<sup>2+</sup> Level in the Endoplasmic Reticulum Restores Abnormal Endogenous F508del‐CFTR Trafficking in Airway Epithelial Cells

Norez, Caroline; Antigny, Fabrice; Becq, Frédéric; Vandebrouck, Clarisse

doi:10.1111/j.1600-0854.2006.00409.x

Cited by 69 publications

(83 citation statements)

References 57 publications

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“…Many of the chemical compounds that have been proposed are on the basis of the observation that function of the ER is intrinsically dependent on calcium concentrations. Thus, maintaining low calcium levels in the ER using the calcium pump inhibitor thapsigargin or other chemicals allows to correct abnormal protein trafficking of ⌬F508 CFTR (23,35) of certain mutants of the V2 vasopressin receptor (36) or of LQT2 channels (25). Another agent, 4-PB, is also able to functionally rescue a number of trafficdefective mutant membrane proteins, including ⌬F508 CFTR (22,33), mutants of the bone morphogenic protein receptor (27), of the epithelial sodium channel (37), the low-density lipoprotein receptor (26), ATP8B1 (38), and the ABC transporter ABCB11 responsible for biliary secretion of bile salts (24).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Gautherot

Durand‐Schneider

Delautier

et al. 2012

Journal of Biological Chemistry

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Background: Mutations of ABCB4, a transporter highly homologous to ABCB1, cause severe liver disease. Results: The I541F mutation induces misfolding and intracellular retention that is rescued by the ABCB1-competitive substrate cyclosporin A but not by modulating the chaperones calnexin or Hsp/Hsc70. Conclusion: Pharmacological chaperones are potential therapeutic tools for ABCB4 misfolded mutants. Significance: This opens perspectives to treat ABCB4-linked genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Gautherot

Durand‐Schneider

Delautier

et al. 2012

Journal of Biological Chemistry

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“…Cl À currents were first recorded in resting cells (see Fig. 2A-D, top traces) and after stimulation by forskolin/genistein [11] (see Fig. 2A-…”

Section: Rescue Of Functional Delf508-cftr By Miglustatmentioning

confidence: 99%

“…Abbreviations: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; Cst, Castanospermine; ER, endoplasmic reticulum; Isc, short-circuit current; NB-DNJ, N-butyldeoxynojirimycin; NB-DGJ, N-butyldeoxygalactonojirimycin I) efflux technique as described [11]. All chemicals are from Sigma Chemicals (St. Louis, MO) exept NB-DNJ and NB-DGJ (Toronto Research Chemicals, Canada), forskolin and genistein (PKC Pharmaceuticals, USA).…”

Section: Functional Assaymentioning

confidence: 99%

“…The chaperone calnexin is a ER lectin-like protein binding monoglucosylated oligosaccharides, i.e., N-linked glycans of the form GlcNAc2Man9Glc1 resulting from the removal of the two outer glucoses by glucosidases [8][9][10]. Recent evidences suggest that inhibitors of ER calcium pumps correct the delF508 trafficking defect through partial inhibition of delF508-CFTR/calnexin interaction [11,12]. Moreover, overexpression of calnexin leads to greater stability of delF508 in the ER [13] and a truncated form of calnexin partially reversed the misprocessing of functional delF508-CFTR [14].…”

Section: Introductionmentioning

confidence: 99%

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Rescue of functional delF508‐CFTR channels in cystic fibrosis epithelial cells by the α‐glucosidase inhibitor miglustat

et al. 2006

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In the disease cystic fibrosis (CF), the most common mutation delF508 results in endoplasmic reticulum retention of misfolded CF gene proteins (CFTR). We show that the a-1,2-glucosidase inhibitor miglustat (N-butyldeoxynojirimycin, NB-DNJ) prevents delF508-CFTR/calnexin interaction and restores cAMP-activated chloride current in epithelial CF cells. Moreover, miglustat rescues a mature and functional delF508-CFTR in the intestinal crypts of ileal mucosa from delF508 mice. Since miglustat is an orally active orphan drug (Zavesca Ò ) prescribed for the treatment of Gaucher disease, our findings provide the basis for future clinical evaluation of miglustat in CF patients.

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“…19 All experiments were performed with a Multi-PROBE Ilex robotic liquid handling system (Perkin Elmer Life Sciences, Courtaboeuf, France).…”

Section: Iodide Efflux Experimentsmentioning

confidence: 99%

Orphan Missense Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator

Fresquet

Clément

Norez

et al. 2011

The Journal of Molecular Diagnostics

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More than 1860 mutations have been found within the human cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence. These mutations can be classified according to their degree of severity in CF disease. Although the most common mutations are well characterized, few data are available for rare mutations. Thus, genetic counseling is particularly difficult when fetuses or patients with CF present these orphan variations. We describe a threestep in vitro assay that can evaluate rare missense CFTR mutation consequences to establish a correlation between genotype and phenotype. By using a green fluorescent protein-tagged CFTR construct, we expressed mutated proteins in COS-7 cells. CFTR trafficking was visualized by confocal microscopy, and the cellular localization of CFTR was determined using intracellular markers. We studied the CFTR maturation process using Western blot analysis and evaluated CFTR channel activity by automated iodide efflux assays. Of six rare mutations that we studied, five have been isolated in our laboratory. The cellular and functional impact that we observed in each case was compared with the clinical data concerning the patients in whom we encountered these mutations. In conclusion, we propose that performing this type of analysis for orphan CFTR missense mutations can improve CF genetic counseling. Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in the white population, with an incidence of approximately 1 in 3500. It results from mutations in the CF transmembrane conductance regulator (CFTR) gene 1,2 that encodes a chloride channel normally expressed at the apical membrane of epithelial cells. 3,4 CFTR is a member of the ATP-binding cassette transporter family. It contains two repeated units composed of a membrane-spanning domain, which includes six transmembrane helices, and a nucleotide-binding domain, which harbors an ATP-binding and hydrolysis site. 5 Both halves are joined by a specific cytoplasmic regulator (R) domain, whose phosphorylation by protein kinase A activates the outward anionic channel activity. 6,7 To date, Ͼ1860 mutations identified within the human CFTR sequence are listed in the CF mutation database (http://www.genet.sickkids.on.ca/Home.html, last accessed March 8, 2011). These mutations can be divided into six classes, according to the mechanism that disrupts CFTR function 8,9 : absence of the protein at the apical plasma membrane because of i) defective protein synthesis or ii) impaired maturation leading to protein degradation, iii) defective regulation of CFTR channel activity, iv) altered ionic selectivity and conductance, v) lowered CFTR mRNA amount, and vi) decreased protein stability.The most common mutation, F508del, is a class II mutation. It is carried by 90% of patients with CF, on at least one allele, and it leads to a severe CF phenotype. In our laboratory, we use the Elucigene CF30 Kit (Gen-Probe, Inc., San Diego, CA), which has been approved in the French national neonatal CF screening program for rou...

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Maintaining Low Ca²⁺ Level in the Endoplasmic Reticulum Restores Abnormal Endogenous F508del‐CFTR Trafficking in Airway Epithelial Cells

Cited by 69 publications

References 57 publications

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Rescue of functional delF508‐CFTR channels in cystic fibrosis epithelial cells by the α‐glucosidase inhibitor miglustat

Orphan Missense Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator

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Maintaining Low Ca2+ Level in the Endoplasmic Reticulum Restores Abnormal Endogenous F508del‐CFTR Trafficking in Airway Epithelial Cells

Cited by 69 publications

References 57 publications

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Rescue of functional delF508‐CFTR channels in cystic fibrosis epithelial cells by the α‐glucosidase inhibitor miglustat

Orphan Missense Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator

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Maintaining Low Ca²⁺ Level in the Endoplasmic Reticulum Restores Abnormal Endogenous F508del‐CFTR Trafficking in Airway Epithelial Cells