Identification of Allelic Variants of Pendrin (SLC26A4) with Loss and Gain of Function

Dossena, Silvia; Bizhanova, Aigerim; Nofziger, Charity; Bernardinelli, Emanuele; Ramsauer, Josef; Kopp, Peter; Paulmichl, Markus

doi:10.1159/000335108

Cited by 43 publications

(44 citation statements)

References 52 publications

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“…The functional test was performed as already described [32,33,34,35], with adaptations allowing the use of a multiplate reader [36,37]. As a high transfection efficiency is an essential prerequisite, HEK 293 Phoenix cells, in which transfection efficiencies of ∼90% are obtained, are particularly suitable for this approach.…”

Section: Methodsmentioning

confidence: 99%

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Procino

Milano

Tamma

et al. 2013

Cell Physiol Biochem

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Background: We recently reported that aquaporin 5 (AQP5), a water channel never identified in the kidney before, co-localizes with pendrin at the apical membrane of type-B intercalated cells in the kidney cortex. Since co-expression of AQP5 and pendrin in the apical membrane domain is a common feature of several other epithelia such as cochlear and bronchial epithelial cells, we evaluated here whether this strict membrane association may reflect a co-regulation of the two proteins. To investigate this possibility, we analyzed AQP5 and pendrin expression and trafficking in mice under chronic K⁺ depletion, a condition that results in an increased ability of renal tubule to reabsorb bicarbonate, often leads to metabolic alkalosis and is known to strongly reduce pendrin expression. Methods: Mice were housed in metabolic cages and pair-fed with either a standard laboratory chow or a K⁺-deficient diet. AQP5 abundance was assessed by western blot in whole kidney homogenates and AQP5 and pendrin were localized by confocal microscopy in kidney sections from those mice. In addition, the short-term effect of changes in external pH on pendrin trafficking was evaluated by fluorescence resonance energy transfer (FRET) in MDCK cells, and the functional activity of pendrin was tested in the presence and absence of AQP5 in HEK 293 Phoenix cells. Results: Chronic K⁺ depletion caused a strong reduction in pendrin and AQP5 expression. Moreover, both proteins shifted from the apical cell membrane to an intracellular compartment. An acute pH shift from 7.4 to 7.0 caused pendrin internalization from the plasma membrane. Conversely, a pH shift from 7.4 to 7.8 caused a significant increase in the cell surface expression of pendrin. Finally, pendrin ion transport activity was not affected by co-expression with AQP5. Conclusions: The co-regulation of pendrin and AQP5 membrane expression under chronic K⁺-deficiency indicates that these two molecules could cooperate as an osmosensor to rapidly detect and respond to alterations in luminal fluid osmolality.

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Section: Methodsmentioning

confidence: 99%

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Procino

Milano

Tamma

et al. 2013

Cell Physiol Biochem

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“…Thus, this may indicate a potentially important role for the comorbid state of asthma and hypertension. In particle, among these top genes TLR4 and ADRB2 (2nd and 6th place in Table 1) are directly discussed in the literature in the context of the comorbidity of asthma and hypertension [21][22][23][24]26]. TLR4 is involved in activation of the innate immune system via the NF-κB signalling pathway along with the up-regulation of inflammatory cytokine production.…”

Section: Prioritization Of Candidate Genesmentioning

confidence: 99%

“…Polymorphisms in b-adrenergic receptor genes are associated with the risk of hypertension and bronchial asthma [18][19][20]. It is assumed that mutations in the SLC26A4 gene can impact the pathogenesis of bronchial asthma and hypertension and, as such, the comorbidity of these diseases [21][22][23][24]. The SLC26A4 gene codes the pendrin protein with Cl-/HCO3-exchanger activity [25].…”

Section: Introductionmentioning

confidence: 99%

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

et al. 2018

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Background: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or~22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. Results: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension -713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system.

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“…HCO 3 - secretion via pendrin is accompanied by intracellular acidification [27]. To evaluate whether the increased abundance of pendrin at the plasma membrane upon cAMP/PKA activation is paralleled by an increase in its activity, real-time measurements of intracellular pH were performed.…”

Section: Resultsmentioning

confidence: 99%

A FRET-Based Approach for Quantitative Evaluation of Forskolin-Induced Pendrin Trafficking at the Plasma Membrane in Bronchial NCI H292 Cells

Tamma

Ranieri²,

Dossena³

et al. 2013

Cell Physiol Biochem

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Background: Human pendrin (SLC26A4, PDS) is an integral membrane protein acting as an electroneutral anion exchanger. Loss of function mutations in pendrin protein cause Pendred syndrome, a disorder characterized by sensorineural deafness and a partial iodide organification defect that may lead to thyroid goiter. Additionally, pendrin up-regulation could play a role in the pathogenesis of several diseases including bronchial asthma and chronic obstructive pulmonary disease (COPD). Therefore, monitoring the plasma membrane abundance and trafficking of pendrin in the context of a living cell is crucially important. Methods: Trafficking of pendrin to the plasma membrane was monitored by fluorescence resonance energy transfer (FRET), a physical phenomenon occurring between two fluorophores (the FRET donor and acceptor) located in close spatial proximity. Because the efficiency of the energy transfer is inversely proportional to the sixth power of the distance between donor and acceptor, FRET is extremely sensitive to small changes in distance between the donor and acceptor and is therefore a powerful tool to determine protein-protein interactions. Results: FRET studies revealed that forskolin-induced cAMP production is associated with a significant increase of pendrin expression at plasma membrane, which is paralleled by a decrease in intracellular pH. Pendrin transposition to the membrane is accompanied with a partial depolymerization of actin cytoskeleton via Rho-GTPase inhibition. Conclusion: Trafficking to the plasma membrane is critical in the regulation of pendrin activity. Therefore, reliable tools for monitoring and quantifying this phenomenon are highly desirable.

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Identification of Allelic Variants of Pendrin (SLC26A4) with Loss and Gain of Function

Cited by 43 publications

References 52 publications

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

A FRET-Based Approach for Quantitative Evaluation of Forskolin-Induced Pendrin Trafficking at the Plasma Membrane in Bronchial NCI H292 Cells

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