High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease

Divac, Aleksandra; Nikolić, Aleksandra; Mitic-Milikic, Marija; Nagorni-Obradović, Ljudmila; Petrovic-Stanojevic, Natasa; Dopudja-Pantic, Vesna; Nadaskic, Ruzica; Savić, Ana; Radojković, Dragica

doi:10.1016/j.jcf.2004.05.049

Cited by 24 publications

(23 citation statements)

References 18 publications

(16 reference statements)

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“…Thus, the fact that p.R75Q is located at the hinge between the N-terminal CFTR cytosolic tail and the first segment of MSD1 may involve some degree of structural interdomain flexibility. Our data seem to corroborate previous results from genotype-clinical phenotype correlations [Divac et al, 2004;Ravnik-Glavac et al, 2000;Ziedalski et al, 2006], leading to the p.R75Q variant's consideration as a polymorphism [Nikolic et al, 2006].…”

Section: Cytosolic N-terminal Variantssupporting

confidence: 90%

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

et al. 2008

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Over 1,500 cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence variations have been identified in patients with cystic fibrosis (CF) and related disorders involving an impaired function of the CFTR chloride channel. However, detailed structure-function analyses have only been established for a few of them. This study aimed evaluating the impact of eight N-terminus CFTR natural missense changes on channel behavior. By site-directed mutagenesis, we generated four CFTR variants in the N-terminal cytoplasmic tail (p.P5L, p.S50P, p.E60K, and p.R75Q) and four in the first transmembrane segment of membrane-spanning domain 1 (p.G85E/V, p.Y89C, and p.E92K). Immunoblot analysis revealed that p.S50P, p.E60K, p.G85E/V, and p.E92K produced only core-glycosylated proteins. Immunofluorescence and whole cell patch-clamp confirmed intracellular retention, thus reflecting a defect of CFTR folding and/or trafficking. In contrast, both p.R75Q and p.Y89C had a glycosylation pattern and a subcellular distribution comparable to the wild-type CFTR, while the percentage of mature p.P5L was considerably reduced, suggesting a major biogenesis flaw on this channel. Nevertheless, whole-cell chloride currents were recorded for all three variants. Single-channel patch-clamp analyses revealed that the channel activity of p.R75Q appeared similar to that of the wild-type CFTR, while both p.P5L and p.Y89C channels displayed abnormal gating. Overall, our results predict a major impact of the CFTR missense variants analyzed, except p.R75Q, on the CF phenotype and highlight the importance of the CFTR N-terminus on channel physiology.

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Section: Cytosolic N-terminal Variantssupporting

confidence: 90%

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

et al. 2008

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“…30 The increased frequency of this variant was also observed in Serbian patients with chronic obstructive pulmonary disease. 31 The alleles of Tn polymorphic locus are not considered to be disease-causing mutations, but they affect CFTR mRNA splicing and can be associated with some mild clinical presentations. The c.1210-12T [7] and c.1210-12T [9] alleles are considered normal, since they generate sufficient amount of functional CFTR mRNA to prevent the development of the disease.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Milošević

Nikolić²,

Rankov³

et al. 2013

Pediatric Allergy, Immunology, and Pulmonology

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“…In CF, mutations of the gene encoding CFTR are associated with a significant decrease in epithelial Cl 2 secretion, excessive Na 1 absorption (8), and decreased paracellular permeability (5,6). This effect is mimicked in chronic obstructive pulmonary disease (COPD) and chronic bronchitis (9)(10)(11)(12). These diseases resemble mild CF, especially during disease exacerbations, when additional insults, such as inflammation, take a toll on the system.…”

mentioning

confidence: 99%

Transforming Growth Factor-β1 and Cigarette Smoke Inhibit the Ability of β₂-Agonists to Enhance Epithelial Permeability

Unwalla¹,

Ivonnet²,

Dennis³

et al. 2015

Am J Respir Cell Mol Biol

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Chronic bronchitis, caused by cigarette smoke exposure, is characterized by mucus hypersecretion and reduced mucociliary clearance (MCC). Effective MCC depends, in part, on adequate airway surface liquid. Cystic fibrosis transmembrane conductance regulator (CFTR) provides the necessary osmotic gradient for serosal to mucosal fluid transport through its ability to both secrete Cl 2 and regulate paracellular permeability, but CFTR activity is attenuated in chronic bronchitis and in smokers. b 2 -adrenergic receptor (b 2 -AR) agonists are widely used for managing chronic obstructive pulmonary disease, and can activate CFTR, stimulate ciliary beat frequency, and increase epithelial permeability, thereby stimulating MCC. Patients with chronic airway diseases and cigarette smokers demonstrate increased transforming growth factor (TGF)-b1 signaling, which suppresses b 2 -agonist-mediated CFTR activation and epithelial permeability increases. Restoring CFTR function in these diseases can restore the ability of b 2 -agonists to enhance epithelial permeability. Human bronchial epithelial cells, fully redifferentiated at the air-liquid interface, were used for 14 C mannitol flux measurements, Ussing chamber experiments, and quantitative RT-PCR. b 2 -agonists enhance epithelial permeability by activating CFTR via the b 2 -AR/adenylyl cyclase/cAMP/ protein kinase A pathway. TGF-b1 inhibits b 2 -agonist-mediated CFTR activation and epithelial permeability enhancement. Although TGF-b1 down-regulates both b 2 -AR and CFTR mRNA, functionally it only decreases CFTR activity. Cigarette smoke exposure inhibits b 2 -agonist-mediated epithelial permeability increases, an effect reversed by blocking TGF-b signaling. b 2 -agonists enhance epithelial permeability via CFTR activation. TGF-b1 signaling inhibits b 2 -agonist-mediated CFTR activation and subsequent increased epithelial permeability, potentially limiting the ability of b 2 -agonists to facilitate paracellular transport in disease states unless TGF-b1 signaling is inhibited.

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High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease

Cited by 24 publications

References 18 publications

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Transforming Growth Factor-β1 and Cigarette Smoke Inhibit the Ability of β₂-Agonists to Enhance Epithelial Permeability

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High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease

Cited by 24 publications

References 18 publications

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Transforming Growth Factor-β1 and Cigarette Smoke Inhibit the Ability of β2-Agonists to Enhance Epithelial Permeability

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Transforming Growth Factor-β1 and Cigarette Smoke Inhibit the Ability of β₂-Agonists to Enhance Epithelial Permeability