Late Breaking Abstract - 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). To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary <italic>Pseudomonas aeruginosa</italic> 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 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 bi-allelic pathogenic variants in <italic>WFDC2</italic> in 11 individuals from 10 unrelated families originating globally. Expression of <italic>WFDC2</italic> 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 <italic>WFDC2</italic>-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. <italic>WFDC2</italic> dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways.

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Published
2024-09-14
DOI
https://doi.org/10.1183/13993003.congress-2024.oa1984
Primary Topic
Tracheal and airway disorders
Type
article
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Late Breaking Abstract - Recessively inherited deficiency of secreted WFDC2 (HE4) causes nasal polyposis and bronchiectasis

Heymut Omran, Niels W. Rutjes, Marius Ueffing, Kai Wohlgemuth et al.
Tracheal and airway disorders
article

Late Breaking Abstract - Recessively inherited deficiency of secreted WFDC2 (HE4) causes nasal polyposis and bronchiectasis

Heymut Omran, Niels W. Rutjes, Marius Ueffing, Kai Wohlgemuth, Saskia M Maas, Achim G. Beule, Sebastian George, Rim Hjeij, Julia König, Agathe Ceppe, Karsten Boldt, Morgane Fierville, Tabea Nöthe-Menchen, Heike Olbrich, Hong Dang, Pascal Barbry, Hong Luo, Laure‐Emmanuelle Zaragosi, Patrick R Sears, Matthew R. Markovetz, Sabine Kliesch, Michael R. Knowles, Yuan‐Ping Pang, Tarek El-Desoky, Thomas W. Ferkol, Amanda Smith, Gerard W. Dougherty, David B. Hill, Eric G. Haarman, Niki T. Loges, Johanna Raidt, Lawrence E. Ostrowski, Diana Bracht, Ting Guo, Maimoona A. Zariwala, Hoda Rizk, Katrin Dahlke, Peadar G. Noone, Weining Yin, Andre Schramm, Kenneth N. Olivier
article en

Abstract

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). To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary <italic>Pseudomonas aeruginosa</italic> 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 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 bi-allelic pathogenic variants in <italic>WFDC2</italic> in 11 individuals from 10 unrelated families originating globally. Expression of <italic>WFDC2</italic> 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 <italic>WFDC2</italic>-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. <italic>WFDC2</italic> dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways.

University of North Carolina at Chapel Hill (US), Mayo Clinic (US), Central South University (CN), Mansoura University (EG), University of Münster (DE), Emma Kinderziekenhuis (NL), University Hospital Münster (DE), Second Xiangya Hospital of Central South University (CN), Institut de Pharmacologie Moléculaire et Cellulaire (FR), University of Tübingen (DE)
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Tracheal and airway disorders
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