Characterization of SLC26A9 in Patients with CF-Like Lung Disease

ABSTRACT 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. We report the functional characterization of 2 mutations in SLC26A9 evidenced in patients presenting with idiopathic bronchiectasis. p.Arg575Trp and p.Val486Ile decrease SLC26A9‐mediated chloride (Cl‐) current in Xenopus laevis oocytes. Additionally, p.Arg575Trp also prevents SLC26A9‐mediated CFTR activation (see CFTR‐mediated currents in Xenopus Laevis oocytes expressing either CFTR alone or CFTR and SLC26A9‐WT or SLC26A9‐p.Arg575Trp). Further structure‐function analysis led us to propose a site on the SLC26A9‐STAS domain for the CFTR‐SLC26A9 interaction. Such mutations may 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.