Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease

Fajac, Isabelle; Viel, Marion; Gaitch, Natacha; Hubert, D.; Bienvenu, Thierry

doi:10.1183/09031936.00057309

Cited by 24 publications

(13 citation statements)

References 8 publications

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“…Such assumption is supported by descriptions of CF‐like pulmonary diseases in patients carrying only one or even none CFTR mutations, strongly suggesting that other Cl − channelopathies may be relevant for bronchiectasis etiology [Bienvenu et al., ; Girodon et al., ; Gonska et al., ; Groman et al., ]. Therefore, it is tempting to speculate that in patients with bronchiectasis, SLC26A9 might play the role of a modifier deleterious gene, acting in trans with other genes involved in ASL hydration, such as CFTR [Bombieri et al., ], ENaC [Fajac et al., ] or yet other unknown genes. In contrast, SLC26A9 might not be deleterious at the heterozygote state, as shown by the fact that p.Val486Ile was identified both in a patient with chronic lung disease but also in her unaffected brother.…”

Section: Discussionmentioning

confidence: 97%

Characterization of SLC26A9 in Patients with CF-Like Lung Disease

et al. 2013

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Diffuse bronchiectasis is a common problem in respiratory clinics. We hypothesized that mutations in the solute carrier 26A9 (SLC26A9) gene, encoding for a chloride (Cl(-)) transporter mainly expressed in lungs, may lead to defects in mucociliary clearance. We describe two missense variants in the SLC26A9 gene in heterozygote patients presenting with diffuse idiopathic bronchiectasis : p.Arg575Trp, identified in a patient also heterozygote for p.Phe508del in the CFTR gene; and p.Val486Ile. Expression of both mutants in Xenopus laevis oocytes abolished SLC26A9-mediated Cl(-) conductance without decreasing protein membrane expression. Coexpression of CFTR with SLC26A9-p.Val486Ile resulted in a significant increase in the Cl(-) current induced by PKA stimulation, similar to that obtained in oocytes expressing CFTR and SLC26A9-WT. In contrast, coexpression of CFTR with SLC26A9-p.Arg575Trp inhibited SLC26A9-enhanced CFTR activation upon PKA. Further structure-function analyses led us to propose a site encompassing Arg575 in the SLC26A9-STAS domain for CFTR-SLC26A9 interaction. We hypothesize that SLC26A9-p.Arg575Trp prevented SLC26A9-mediated functional activation of CFTR by altering SLC26A9-CFTR interaction. Although we cannot confirm that these mutations by themselves are deleterious, we propose that they trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl(-) transport alteration across the respiratory mucosa, based on functional inhibition of CFTR.

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Section: Discussionmentioning

confidence: 97%

Characterization of SLC26A9 in Patients with CF-Like Lung Disease

et al. 2013

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“…In accord with its role in these processes, improper ENaC function is implicated in several disorders. There is a growing body of evidence that enhanced ENaC activity in the airways of individuals with cystic fibrosis contributes to depletion of airway surface liquids resulting in poor mucociliary clearance (1)(2)(3). In the kidney, increased levels of aldosterone activate ENaC and increase the reabsorption of filtered Na ϩ (4).…”

mentioning

confidence: 99%

Allosteric Inhibition of the Epithelial Na+ Channel through Peptide Binding at Peripheral Finger and Thumb Domains

Kashlan

Boyd

Argyropoulos

et al. 2010

Journal of Biological Chemistry

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The epithelial Na ؉ channel (ENaC) mediates the rate-limiting step in transepithelial Na ؉ transport in the distal segments of the nephron and in the lung. ENaC subunits are cleaved by proteases, resulting in channel activation due to the release of inhibitory tracts. Peptides derived from these tracts inhibit channel activity. The mechanism by which these intrinsic inhibitory tracts reduce channel activity is unknown, as are the sites where these tracts interact with other residues within the channel. We performed site-directed mutagenesis in large portions of the predicted periphery of the extracellular region of the ␣ subunit and measured the effect of mutations on an 8-residue inhibitory tract-derived peptide. Our data show that the inhibitory peptide likely binds to specific residues within the finger and thumb domains of ENaC. Pairwise interactions between the peptide and the channel were identified by double mutant cycle experiments. Our data suggest that the inhibitory peptide has a specific peptide orientation within its binding site. Extended to the intrinsic inhibitory tract, our data suggest that proteases activate ENaC by removing residues that bind at the fingerthumb domain interface.The epithelial Na ϩ channel (ENaC) 2 is expressed at the apical surface of Na ϩ -transporting epithelia such as the distal nephron of the kidney, distal colon, and lung alveoli and airway. In conjunction with the Na ϩ /K ϩ -ATPase, ENaC transfers Na ϩ from the luminal to the interstitial space. This transfer is crucial in regulating blood pressure through its role in renal Na ϩ absorption and in regulating airway surface liquid volume and mucociliary clearance through its role in airway Na ϩ absorption. In accord with its role in these processes, improper ENaC function is implicated in several disorders. There is a growing body of evidence that enhanced ENaC activity in the airways of individuals with cystic fibrosis contributes to depletion of airway surface liquids resulting in poor mucociliary clearance (1-3). In the kidney, increased levels of aldosterone activate ENaC and increase the reabsorption of filtered Na ϩ (4). In both instances, increases in channel activity reflect, in part, enhanced channel proteolysis. Proteinuric states, characterized by excessive protein in the urine, are often accompanied by renal Na ϩ retention, volume expansion, and hypertension. Recent work indicates that volume expansion in proteinuric states reflects proteolytic activation of ENaC (5-7).ENaC is a trimer composed of three homologous subunits, ␣, ␤, and ␥ (8, 9). ENaC subunits are members of the much larger ENaC/Degenerin family of ion channel proteins. These channels share a few salient features as follows: 1) most are gated by ligands and/or mechanical forces; 2) they are Na ϩ -permeable and blocked by amiloride, a potassium-sparing diuretic; and 3) each subunit has two transmembrane helices (six transmembrane helices for the full channel), short intracellular N and C termini, and a large extracellular region comprised of sever...

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“…In support of this possibility, it was reported that mouse models with ENaC channel overexpression showed a phenotype reminiscent of CF (Donaldson and Boucher 2007). In fact, some patients with CF-like disease but mutations in only one copy of their CFTR genes were found to carry gain-of-function mutations in ENaC-encoding subunits (Sheridan et al 2005;Azad et al 2009;Fajac et al 2009). …”

Section: Identification Of Cftr Genementioning

confidence: 90%