Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis

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. To identify novel genetic defects in un...

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Published in:	American journal of respiratory and critical care medicine Vol. 210; no. 1; pp. 63 - 76
Main Authors:	Dougherty, Gerard W, Ostrowski, Lawrence E, Nöthe-Menchen, Tabea, Raidt, Johanna, Schramm, Andre, Olbrich, Heike, Yin, Weining, Sears, Patrick R, Dang, Hong, Smith, Amanda J, Beule, Achim G, Hjeij, Rim, Rutjes, Niels, Haarman, Eric G, Maas, Saskia M, Ferkol, Thomas W, Noone, Peadar G, Olivier, Kenneth N, Bracht, Diana C, Barbry, Pascal, Zaragosi, Laure-Emmanuelle, Fierville, Morgane, Kliesch, Sabine, Wohlgemuth, Kai, König, Julia, George, Sebastian, Loges, Niki T, Ceppe, Agathe, Markovetz, Matthew R, Luo, Hong, Guo, Ting, Rizk, Hoda, Eldesoky, Tarek, Dahlke, Katrin, Boldt, Karsten, Ueffing, Marius, Hill, David B, Pang, Yuan-Ping, Knowles, Michael R, Zariwala, Maimoona A, Omran, Heymut
Format:	Journal Article
Language:	English
Published:	United States American Thoracic Society 01-07-2024
Subjects:	Adolescent Adult Bronchiectasis - genetics Bronchiectasis - physiopathology Child Cystic fibrosis Deoxyribonucleic acid DNA Dyskinesia Female Genetics Humans Male Middle Aged Nasal Polyps - genetics Original Ribonucleic acid RNA WAP Four-Disulfide Core Domain Protein 2 Young Adult Pseudomonas infertility chronic airway disease
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Summary:	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. To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary infection. 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. We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 ( ) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of 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 -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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1073-449X 1535-4970 1535-4970
DOI:	10.1164/rccm.202308-1370OC