Characterization of SLC26A9 in Patients with CF-Like Lung Disease

Autor: Thierry Bienvenu, Serge Amselem, Aleksander Edelman, Baya Cherif-Zahar, Philippe Duquesnoy, Jordi Ehrenfeld, Marion Viel, Huguette Lioté, Nicolette Farman, Gabrielle Planelles, Isabelle Sermet-Gaudelus, Delphine Roussel, Annick Thomas, Naziha Bakouh, Rola Abou Taam
Přispěvatelé: Couvet, Sandrine, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Pathogenèse des Virus de l'Hépatite B (PVHB), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biologie et physiopathologie des systèmes intégrés (LBPSI), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Lung Diseases
Male
bronchiectasis
Mutant
Xenopus
Cystic Fibrosis Transmembrane Conductance Regulator
Gene Expression
Cystic fibrosis
[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Antiporters
cystic fibrosis
Xenopus laevis
Missense mutation
Child
Genetics (clinical)
Genetics
Aged
80 and over
biology
Exons
respiratory system
Middle Aged
Phenotype
Sulfate Transporters
Female
Protein Binding
Adult
congenital
hereditary
and neonatal diseases and abnormalities
Adolescent
Mucociliary clearance
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Young Adult
SLC26A9
medicine
Animals
Humans
oocytes
Protein Interaction Domains and Motifs
Aged
Heterozygote advantage
Transporter
medicine.disease
biology.organism_classification
Molecular biology
Peptide Fragments
respiratory tract diseases
Solute carrier family
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Case-Control Studies
Mutation
[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Tomography
X-Ray Computed
Zdroj: Human Mutation
Human Mutation, 2013, 34 (10), pp.1404-1414. ⟨10.1002/humu.22382⟩
ISSN: 1059-7794
1098-1004
DOI: 10.1002/humu.22382⟩
Popis: 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.
Databáze: OpenAIRE
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