title: 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.
authors.affiliation: INSERM U 845, Paris, France; Faculté de Médecine, Université René Descartes, Paris V, Paris, France.
authors.forename: Naziha
authors.initials: N
authors.lastname: Bakouh
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.forename: Annick
authors.initials: A
authors.lastname: Thomas
authors.forename: Jordi
authors.initials: J
authors.lastname: Ehrenfeld
authors.forename: Huguette
authors.initials: H
authors.lastname: Liote
authors.forename: Delphine
authors.initials: D
authors.lastname: Roussel
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
authors.forename: Marion
authors.initials: M
authors.lastname: Viel
authors.forename: Baya
authors.initials: B
authors.lastname: Cherif-Zahar
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.forename: Rola Abou
authors.initials: RA
authors.lastname: Taam
authors.forename: Aleksander
authors.initials: A
authors.lastname: Edelman
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Planelles
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sermet-Gaudelus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017920:Antiporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D008171:Lung Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000076988:Sulfate Transporters; D014057:Tomography, X-Ray Computed; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: D017920:Antiporters; D010446:Peptide Fragments; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: SLC26A9; Xenopus laevis oocytes; bronchiectasis; cystic fibrosis