| Autor: |
Dougherty GW; Department of General Pediatrics., Ostrowski LE; Department of Pediatrics.; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Nöthe-Menchen T; Department of General Pediatrics., Raidt J; Department of General Pediatrics., Schramm A; Department of General Pediatrics., Olbrich H; Department of General Pediatrics., Yin W; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Sears PR; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Dang H; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Smith AJ; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Beule AG; Department of Otorhinolaryngology, and., Hjeij R; Department of General Pediatrics., Rutjes N; Department of Pediatric Pulmonology and Allergy, Emma Children's Hospital, Amsterdam, the Netherlands., Haarman EG; Department of Pediatric Pulmonology and Allergy, Emma Children's Hospital, Amsterdam, the Netherlands., Maas SM; Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands., Ferkol TW; Department of Pediatrics., Noone PG; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center.; Department of Medicine., Olivier KN; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center.; Department of Medicine., Bracht DC; Department of General Pediatrics., Barbry P; Université Côte d'Azur, CNRS, Institut Pharmacologie Moléculaire et Cellulaire, Sophia-Antipolis, France., Zaragosi LE; Université Côte d'Azur, CNRS, Institut Pharmacologie Moléculaire et Cellulaire, Sophia-Antipolis, France., Fierville M; Université Côte d'Azur, CNRS, Institut Pharmacologie Moléculaire et Cellulaire, Sophia-Antipolis, France., Kliesch S; Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Muenster, Muenster, Germany., Wohlgemuth K; Department of General Pediatrics., König J; Department of General Pediatrics., George S; Department of General Pediatrics., Loges NT; Department of General Pediatrics., Ceppe A; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Markovetz MR; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center., Luo H; Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, China., Guo T; Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, China., Rizk H; Department of Pediatrics, Faculty of Medicine, University of Mansoura, Mansoura, Egypt., Eldesoky T; Department of Pediatrics, Faculty of Medicine, University of Mansoura, Mansoura, Egypt., Dahlke K; Institute for Ophthalmic Research and Core Facility for Medical Proteomics, Tübingen, Germany.; Eberhard Karls University Tübingen, Tübingen, Germany; and., Boldt K; Institute for Ophthalmic Research and Core Facility for Medical Proteomics, Tübingen, Germany.; Eberhard Karls University Tübingen, Tübingen, Germany; and., Ueffing M; Institute for Ophthalmic Research and Core Facility for Medical Proteomics, Tübingen, Germany.; Eberhard Karls University Tübingen, Tübingen, Germany; and., Hill DB; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center.; Department of Physics and Astronomy, and., Pang YP; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Knowles MR; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center.; Department of Medicine., Zariwala MA; Marsico Lung Institute/Cystic Fibrosis Research and Treatment Center.; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Omran H; Department of General Pediatrics. |
| Abstrakt: |
Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived cells, cell cultures, and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 ( WFDC2 ) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2 -deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and, thus, secretion of mature WFDC2. Conclusions: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis. |
