Nasal potential difference of carriers of the W493R ENaC variant with non-cystic fibrosis bronchiectasis

Rademacher, Jessica; Schulz, Angela; Hedtfeld, Silke; Stanke, Frauke; Ringshausen, Felix C.; Welte, Tobias; Tümmler, Burkhard

doi:10.1183/13993003.01128-2015

Cited by 6 publications

(3 citation statements)

References 10 publications

(21 reference statements)

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“…In our study, none of the biallelic CFTR variants was identified in healthy subjects; three of six variants (50.0%) that were identified among bronchiectasis patients were novel ENaC variants (including SCNN1A, SCNN1B and SCNN1G), whereas SCNN1B variant was detected in healthy subjects only (Table S4). However, SCNN1A mutations alone might be insufficient to result in bronchiectasis, because only the p.W493R-SCNN1A and p.F61L-SCNN1A mutations predisposed to CF-like lung disease via hyperreactive sodium absorption (27). Gain-offunction (auto-dominant) mutation of ENaC predisposed to CF via increased sodium absorption, whereas loss-offunction (auto-recessive) mutation did not invariably result in airway diseases despite perturbed ion transportation (28,29).…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis

Guan

Liu

et al. 2018

J. Thorac. Dis.

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Section: Discussionmentioning

confidence: 99%

Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis

Guan

Liu

et al. 2018

J. Thorac. Dis.

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“…39 Patients who carry the p.W493R-SCNN1A, a variant that encodes for a hyperactive ENaC channel, have been identified as being at a higher risk of developing bronchiectasis. 40 In 2008 and 2009, Fajac and colleagues investigated whether a defective ENaC protein could be involved in the development of bronchiectasis. They analyzed ENaC-beta and -gamma genes in 55 subjects who had idiopathic bronchiectasis without two mutations in the coding regions of CFTR.…”

Section: Mucociliary Functionmentioning

confidence: 99%

Pathophysiology of Bronchiectasis

Keir

Chalmers

2021

Semin Respir Crit Care Med

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Bronchiectasis is a complex, heterogeneous disorder defined by both a radiological abnormality of permanent bronchial dilatation and a clinical syndrome. There are multiple underlying causes including severe infections, mycobacterial disease, autoimmune conditions, hypersensitivity disorders, and genetic conditions. The pathophysiology of disease is understood in terms of interdependent concepts of chronic infection, inflammation, impaired mucociliary clearance, and structural lung damage. Neutrophilic inflammation is characteristic of the disease, with elevated levels of harmful proteases such as neutrophil elastase associated with worse outcomes. Recent data show that neutrophil extracellular trap formation may be the key mechanism leading to protease release and severe bronchiectasis. Despite the dominant of neutrophilic disease, eosinophilic subtypes are recognized and may require specific treatments. Neutrophilic inflammation is associated with elevated bacterial loads and chronic infection with organisms such as Pseudomonas aeruginosa. Loss of diversity of the normal lung microbiota and dominance of proteobacteria such as Pseudomonas and Haemophilus are features of severe bronchiectasis and link to poor outcomes. Ciliary dysfunction is also a key feature, exemplified by the rare genetic syndrome of primary ciliary dyskinesia. Mucus symptoms arise through goblet cell hyperplasia and metaplasia and reduced ciliary function through dyskinesia and loss of ciliated cells. The contribution of chronic inflammation, infection, and mucus obstruction leads to progressive structural lung damage. The heterogeneity of the disease is the most challenging aspect of management. An understanding of the pathophysiology of disease and their biomarkers can help to guide personalized medicine approaches utilizing the concept of “treatable traits.”

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“…On this side, it has been speculated that bronchiectasis may derive from a complex multifactorial interaction between genetic risk factors and environment. Other genes, so far unidentified, are likely to interact with CFTR activity in the development of the disease; in particular, altered sodium homeostasis due to mutations in ENaC channel is still poorly understood but may play a contributive role [ 55 , 56 ].…”

Section: Implications For Future Researchmentioning

confidence: 99%

When and how ruling out cystic fibrosis in adult patients with bronchiectasis

Gramegna

Aliberti

Seia

et al. 2018

Multidiscip Respir Med

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BackgroundBronchiectasis is the final result of different processes and most of the guidelines advocate for a careful evaluation of those etiologies which might be treated or might change patients’ management, including cystic fibrosis (CF).Main bodyCFTR mutations have been reported with higher frequency in bronchiectasis population. Although ruling out CF is considered as a main step for etiological screening in bronchiectasis, CF testing lacks of a standardized approach both from a research and clinical point of view. In this review a list of most widely used tests in CF is provided.ConclusionsExclusion of CF is imperative for patients with bronchiectasis and CFTR testing should be implemented in usual screening for investigating bronchiectasis etiology. Physicians taking care of bronchiectasis patients should be aware of CFTR testing and its limitations in the adult population. Further studies on CFTR expression in human lung and translational research might elucidate the possible role of CFTR in the pathogenesis of bronchiectasis.

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Nasal potential difference of carriers of the W493R ENaC variant with non-cystic fibrosis bronchiectasis

Cited by 6 publications

References 10 publications

Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis

Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis

Pathophysiology of Bronchiectasis

When and how ruling out cystic fibrosis in adult patients with bronchiectasis

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