Referenced in: none

Automatically associated channels: TRP

Title: Characterization of SLC26A9 in patients with CF-like lung disease.

Authors: Naziha Bakouh, Thierry Bienvenu, Annick Thomas, Jordi Ehrenfeld, Huguette Liote, Delphine Roussel, Philippe Duquesnoy, Nicolette Farman, Marion Viel, Baya Cherif-Zahar, Serge Amselem, Rola Abou Taam, Aleksander Edelman, Gabrielle Planelles, Isabelle Sermet-Gaudelus

Journal, date & volume: Hum. Mutat., 2013 Oct , 34, 1404-14

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24272871

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.