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Journal Articles Human Mutation Year : 2013

Characterization of SLC26A9 in Patients with CF-Like Lung Disease

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Abstract

Diffuse bronchiectasis is a common problemin respiratory clinics. We hypothesized that mutations inthe solute carrier 26A9 (SLC26A9) gene, encoding for achloride (Cl−) transporter mainly expressed in lungs, maylead to defects in mucociliary clearance. We describe twomissense variants in theSLC26A9gene in heterozygotepatients presenting with diffuse idiopathic bronchiectasis: p.Arg575Trp, identified in a patient also heterozygotefor p.Phe508del in theCFTRgene; and p.Val486Ile.Expression of both mutants inXenopus laevisoocytesabolished SLC26A9-mediated Cl−conductance withoutdecreasing protein membrane expression. Coexpressionof CFTR with SLC26A9–p.Val486Ile resulted in a sig-nificant increase in the Cl−current induced by PKAstimulation, similar to that obtained in oocytes express-ing CFTR and SLC26A9–WT. In contrast, coexpres-sion of CFTR with SLC26A9–p.Arg575Trp inhibitedSLC26A9-enhanced CFTR activation upon PKA. Fur-ther structure–function analyses led us to propose a siteencompassing Arg575 in the SLC26A9–STAS domainfor CFTR–SLC26A9 interaction. We hypothesize thatSLC26A9–p.Arg575Trp prevented SLC26A9-mediatedfunctional activation of CFTR by altering SLC26A9–CFTR interaction. Although we cannot confirm that thesemutations by themselves are deleterious, we propose thatthey trigger the pathogenic role of a singleCFTRmuta-tion and provide insight into a novel mechanism of Cl−transport alteration across the respiratory mucosa, basedon functional inhibition of CFTR
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Dates and versions

inserm-03885353 , version 1 (05-12-2022)

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Naziha Bakouh, Thierry Bienvenu, Annick Thomas, Jordi Ehrenfeld, Huguette Liote, et al.. Characterization of SLC26A9 in Patients with CF-Like Lung Disease. Human Mutation, 2013, 34 (10), pp.1404-1414. ⟨10.1002/humu.22382⟩. ⟨inserm-03885353⟩
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