Should diffuse bronchiectasis still be considered a CFTR-related disorder?

Bergougnoux, Anne; Viart, Victoria; Miro, Julie; Bommart, Sébastien; Molinari, Nicolas; Georges, Marie des; Claustres, Mireille; Chiron, R.; Taulan, Magali

doi:10.1016/j.jcf.2015.02.012

Cited by 22 publications

(22 citation statements)

References 32 publications

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“…There is evidence that bronchiectasis may represent a spectrum of CFTR-related disorders as there are increased frequencies of CFTR mutations in patients in various studies [37]. In addition to the associations of CFTR mutant alleles in bronchiectasis, CFTR functional defects have been discovered in patients harboring no-CFTR mutant alleles using sweat chloride and nasal potential difference measurements [38].…”

Section: Acquired Cftr Dysfunction In Asthma and Non-cf Bronchiectasimentioning

confidence: 99%

The therapeutic potential of CFTR modulators for COPD and other airway diseases

Solomon

Rowe

et al. 2017

Current Opinion in Pharmacology

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Airways diseases, especially chronic obstructive pulmonary disease (COPD) and asthma, are common causes of morbidity and mortality worldwide. There is an ongoing unmet need for novel and effective therapies. There is an established pathophysiological link and phenotypic similarity between the chronic bronchitis phenotype of COPD and cystic fibrosis (CF). New evidence suggests that CFTR dysfunction may play a role in other common airways diseases such as COPD, non-atopic asthma and non-CF bronchiectasis. Newly approved and investigational drugs that target both mutant and wild type CFTR channels have provided a new treatment opportunity addressing the mucus defect in pulmonary diseases that share the same pathophysiology with CF.

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Section: Acquired Cftr Dysfunction In Asthma and Non-cf Bronchiectasimentioning

confidence: 99%

The therapeutic potential of CFTR modulators for COPD and other airway diseases

Solomon

Rowe

et al. 2017

Current Opinion in Pharmacology

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“…Interestingly, four variants (c.454A>G, c.523A>G, c.1727G>C, and c.3700A>G) formerly classified as missense variants, that have recently been reclassified as splicing variants based on experimental results (Bergougnoux et al, ; Ramalho et al, ; Raynal et al, and unpublished personal data) were correctly predicted as not affecting the sequence and the 3D structure of the CFTR protein by CYSMA and SIFT, which was not always the case with Polyphen‐2. Conversely, the variant c.2706C>G (S902R), previously reported to cause the total loss of 203 base pairs of exon 15 (Raynal et al, ) has been predicted as deleterious by CYSMA.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…Interestingly, the variants c.454A>G, c.523A>G, c.1727G>C, and c.3700A>G (legacy names M152V, I175V, G576A, and I1234V, respectively) were counted among these false‐negatives due to negative predictions despite their classification as disease‐causing (three CF‐causing, one CFTR ‐RD). Indeed, in vitro functional studies recently published or performed in our own laboratory (Bergougnoux et al, ; Ramalho et al, ; Raynal et al, and unpublished data) allowed to reclassify these four variants as splicing variants. Thus, considering these data, CYSMA sensitivity and specificity increased to reach 92 and 88%, respectively (Figure S1).…”

Section: Software Operation and Output Datamentioning

confidence: 99%

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The CYSMA web server: An example of integrative tool for in silico analysis of missense variants identified in Mendelian disorders

et al. 2019

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Exome sequencing used for molecular diagnosis of Mendelian disorders considerably increases the number of missense variants of unclear significance, whose pathogenicity can be assessed by a variety of prediction tools. As the performance of algorithms may vary according to the datasets, complementary specific resources are needed to improve variant interpretation. As a model, we were interested in the cystic fibrosis transmembrane conductance regulator gene (CFTR) causing cystic fibrosis, in which at least 40% of missense variants are reported. Cystic fibrosis missense analysis (CYSMA) is a new web server designed for online estimation of the pathological relevance of CFTR missense variants. CYSMA generates a set of computationally derived data, ranging from evolutionary conservation to functional observations from three-dimensional structures, provides all available allelic frequencies, clinical observations, and references for functional studies. Compared to software classically used in analysis pipelines on a dataset of 141 well-characterized missense variants, CYSMA was the most efficient tool to discriminate benign missense variants, with a specificity of 85%, and very good sensitivity of 89%. These results suggest that such integrative tools could be adapted to numbers of genes involved in Mendelian disorders to improve the interpretation of missense variants identified in the context of diagnosis. K E Y W O R D S3D models, 3D structures, bioinformatics, cystic fibrosis transmembrane conductance regulator (CFTR), rare missense variants, sequence alignment

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“…The implication of CFTR in diffuse bronchiectasis or nasal polyposis is more controversial [34]; variants in other genes were previously reported as possibly causative. However, the identification of mutations in other genes with sufficient significance remains difficult and needs large patient cohorts.…”

Section: Other Locimentioning

confidence: 99%