Research

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14 pages, 1606 KiB

Open AccessArticle

Integrity and Stability of PTC Bearing CFTR mRNA and Relevance to Future Modulator Therapies in Cystic Fibrosis

by Luka A. Clarke, Vanessa C. C. Luz, Szymon Targowski, Sofia S. Ramalho, Carlos M. Farinha and Margarida D. Amaral

Genes 2021, 12(11), 1810; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111810 - 18 Nov 2021

Cited by 8 | Viewed by 2278

Abstract

Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into [...] Read more.

Major advances have recently been made in the development and application of CFTR (cystic fibrosis transmembrane conductance regulator) mutation class-specific modulator therapies, but to date, there are no approved modulators for Class I mutations, i.e., those introducing a premature termination codon (PTC) into the CFTR mRNA. Such mutations induce nonsense-mediated decay (NMD), a cellular quality control mechanism that reduces the quantity of PTC bearing mRNAs, presumably to avoid translation of potentially deleterious truncated CFTR proteins. The NMD-mediated reduction of PTC-CFTR mRNA molecules reduces the efficacy of one of the most promising approaches to treatment of such mutations, namely, PTC readthrough therapy, using molecules that induce the incorporation of near-cognate amino acids at the PTC codon, thereby enabling translation of a full-length protein. In this study, we measure the effect of three different PTC mutations on the abundance, integrity, and stability of respective CFTR mRNAs, using CFTR specific RT-qPCR-based assays. Altogether, our data suggest that optimized rescue of PTC mutations has to take into account (1) the different steady-state levels of the CFTR mRNA associated with each specific PTC mutation; (2) differences in abundance between the 3′ and 5′ regions of CFTR mRNA, even following PTC readthrough or NMD inhibition; and (3) variable effects on CFTR mRNA stability for each specific PTC mutation. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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16 pages, 1399 KiB

Open AccessArticle

Prenatal Ultrasound Suspicion of Cystic Fibrosis in a Multiethnic Population: Is Extensive CFTR Genotyping Needed?

by Chadia Mekki, Abdel Aissat, Véronique Mirlesse, Sophie Mayer Lacrosniere, Elsa Eche, Annick Le Floch, Sandra Whalen, Cecile Prud’Homme, Christelle Remus, Benoit Funalot, Vanina Castaigne, Pascale Fanen and Alix de Becdelièvre

Genes 2021, 12(5), 670; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050670 - 29 Apr 2021

Cited by 4 | Viewed by 3144

Abstract

In families without a Cystic Fibrosis (CF) history, fetal ultrasound bowel abnormalities can unexpectedly reveal the disease. Isolated or in association, the signs can be fetal bowel hyperechogenicity, intestinal loop dilatation and non-visualization of fetal gallbladder. In these cases, search for CF transmembrane [...] Read more.

In families without a Cystic Fibrosis (CF) history, fetal ultrasound bowel abnormalities can unexpectedly reveal the disease. Isolated or in association, the signs can be fetal bowel hyperechogenicity, intestinal loop dilatation and non-visualization of fetal gallbladder. In these cases, search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the recommended diagnostic practices, with a search for frequent mutations according to ethnicity, and, in case of the triad of signs, with an exhaustive study of the gene. However, the molecular diagnosis remains a challenge in populations without well-known frequent pathogenic variants. We present a multiethnic cohort of 108 pregnancies with fetal bowel abnormalities in which the parents benefited from an exhaustive study of the CFTR gene. We describe the new homozygous p.Cys1410* mutation in a fetus of African origin. We did not observe the most frequent p.Phe508del mutation in our cohort but evidenced variants undetected by our frequent mutations kit. Thanks to the progress of sequencing techniques and despite the difficulties of interpretation occasionally encountered, we discuss the need to carry out a comprehensive CFTR study in all patients in case of fetal bowel abnormalities. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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13 pages, 4081 KiB

Open AccessArticle

DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

by Fanny Pineau, Davide Caimmi, Sylvie Taviaux, Maurane Reveil, Laura Brosseau, Isabelle Rivals, Margot Drevait, Isabelle Vachier, Mireille Claustres, Raphaël Chiron and Albertina De Sario

Genes 2021, 12(3), 441; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12030441 - 19 Mar 2021

Cited by 3 | Viewed by 2166

Abstract

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide [...] Read more.

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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Review

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13 pages, 1473 KiB

Open AccessReview

Metaproteomics to Decipher CF Host-Microbiota Interactions: Overview, Challenges and Future Perspectives

by Pauline Hardouin, Raphael Chiron, Hélène Marchandin, Jean Armengaud and Lucia Grenga

Genes 2021, 12(6), 892; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060892 - 09 Jun 2021

Cited by 11 | Viewed by 2715

Abstract

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, triggering dysfunction of the anion channel in several organs including the lung and gut. The main cause of morbidity and mortality is chronic [...] Read more.

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, triggering dysfunction of the anion channel in several organs including the lung and gut. The main cause of morbidity and mortality is chronic infection. The microbiota is now included among the additional factors that could contribute to the exacerbation of patient symptoms, to treatment outcome, and more generally to the phenotypic variability observed in CF patients. In recent years, various omics tools have started to shed new light on microbial communities associated with CF and host–microbiota interactions. In this context, proteomics targets the key effectors of the responses from organisms, and thus their phenotypes. Recent advances are promising in terms of gaining insights into the CF microbiota and its relation with the host. This review provides an overview of the contributions made by proteomics and metaproteomics to our knowledge of the complex host–microbiota partnership in CF. Considering the strengths and weaknesses of proteomics-based approaches in profiling the microbiota in the context of other diseases, we illustrate their potential and discuss possible strategies to overcome their limitations in monitoring both the respiratory and intestinal microbiota in sample from patients with CF. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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20 pages, 729 KiB

Open AccessReview

Quantification of Phenotypic Variability of Lung Disease in Children with Cystic Fibrosis

by Mirjam Stahl, Eva Steinke and Marcus A. Mall

Genes 2021, 12(6), 803; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060803 - 25 May 2021

Cited by 6 | Viewed by 2345

Abstract

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those [...] Read more.

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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21 pages, 1115 KiB

Open AccessEditor’s ChoiceReview

Achromobacter xylosoxidans and Stenotrophomonas maltophilia: Emerging Pathogens Well-Armed for Life in the Cystic Fibrosis Patients’ Lung

by Quentin Menetrey, Pauline Sorlin, Estelle Jumas-Bilak, Raphaël Chiron, Chloé Dupont and Hélène Marchandin

Genes 2021, 12(5), 610; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050610 - 21 Apr 2021

Cited by 40 | Viewed by 4770

Abstract

In patients with cystic fibrosis (CF), the lung is a remarkable ecological niche in which the microbiome is subjected to important selective pressures. An inexorable colonization by bacteria of both endogenous and environmental origin is observed in most patients, leading to a vicious [...] Read more.

In patients with cystic fibrosis (CF), the lung is a remarkable ecological niche in which the microbiome is subjected to important selective pressures. An inexorable colonization by bacteria of both endogenous and environmental origin is observed in most patients, leading to a vicious cycle of infection–inflammation. In this context, long-term colonization together with competitive interactions among bacteria can lead to over-inflammation. While Pseudomonas aeruginosa and Staphylococcus aureus, the two pathogens most frequently identified in CF, have been largely studied for adaptation to the CF lung, in the last few years, there has been a growing interest in emerging pathogens of environmental origin, namely Achromobacter xylosoxidans and Stenotrophomonas maltophilia. The aim of this review is to gather all the current knowledge on the major pathophysiological traits, their supporting mechanisms, regulation and evolutionary modifications involved in colonization, virulence, and competitive interactions with other members of the lung microbiota for these emerging pathogens, with all these mechanisms being major drivers of persistence in the CF lung. Currently available research on A. xylosoxidans complex and S. maltophilia shows that these emerging pathogens share important pathophysiological features with well-known CF pathogens, making them important members of the complex bacterial community living in the CF lung. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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15 pages, 682 KiB

Open AccessEditor’s ChoiceReview

Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine

by Afsoon Sepahzad, Deborah J. Morris-Rosendahl and Jane C. Davies

Genes 2021, 12(4), 562; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040562 - 13 Apr 2021

Cited by 19 | Viewed by 4230

Abstract

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in [...] Read more.

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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8 pages, 547 KiB

Open AccessReview

Modulation of Ion Transport to Restore Airway Hydration in Cystic Fibrosis

by James A. Reihill, Lisa E. J. Douglas and S. Lorraine Martin

Genes 2021, 12(3), 453; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12030453 - 22 Mar 2021

Cited by 7 | Viewed by 3265

Abstract

Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl⁻ channel. Loss of Cl⁻ secretion across the apical membrane of airway lining epithelial cells results in [...] Read more.

Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl⁻ channel. Loss of Cl⁻ secretion across the apical membrane of airway lining epithelial cells results in dehydration of the airway surface liquid (ASL) layer which impairs mucociliary clearance (MCC), and as a consequence promotes bacterial infection and inflammation of the airways. Interventions that restore airway hydration are known to improve MCC. Here we review the ion channels present at the luminal surface of airway epithelial cells that may be targeted to improve airway hydration and MCC in CF airways. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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