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Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases
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Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 10546

Special Issue Editor

Prof. Dr. Tsukasa Okiyoneda

E-Mail Website
Guest Editor
Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1337, Japan
Interests: cystic fibrosis; cystic fibrosis transmembrane conductance regulator (CFTR); chloride channel

Special Issue Information

Dear Colleagues, 

Cystic fibrosis (CF) is caused by the congenital loss of function of CF transmembrane conductance regulator (CFTR), a cAMP-regulated Cl- channel expressing at the plasma membrane of epithelial cells. Dysregulated CFTR function caused by genetic and/or environmental stresses could participate in the pathogenesis of diseases including chronic obstructive pulmonary disease (COPD), asthma, and bronchiectasis. Thus, understanding the molecular mechanism of dysregulated CFTR function can help us to develop novel therapeutic approaches for the CFTR-related diseases associated with CFTR mutations and polymorphisms. Moreover, in addition to traditional small-molecule CFTR modulators, new chemical modalities including oligonucleotides, molecular glues, and gene therapy may provide novel therapeutic approaches for CFTR-related diseases. 

This Special Issue on “Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases” will gather reviews and original articles focused on the molecular pathology of CFTR-related diseases and novel therapeutic approaches at basic, translational, and clinical levels to provide expert insights and perspectives on advances in the field.

Prof. Dr. Tsukasa Okiyoneda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cystic fibrosis
  • CFTR
  • CFTR-related disease
  • therapy
  • molecular pathology
  • COPD
  • polymorphism
  • rare mutation

Published Papers (5 papers)

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Research

11 pages, 538 KiB  
Article
Pathogenic Variants and Genotypes of the CFTR Gene in Russian Men with Cystic Fibrosis and CBAVD Syndrome
by Vyacheslav Chernykh, Stanislav Krasovsky, Olga Solovova, Tagui Adyan, Anna Stepanova, Ekaterina Marnat, Maria Shtaut, Anna Sedova, Tatyana Sorokina, Tatyana Beskorovainaya, Elena Kondratyeva, Olga Shchagina and Aleksandr Polyakov
Int. J. Mol. Sci. 2023, 24(22), 16287; https://doi.org/10.3390/ijms242216287 - 14 Nov 2023
Cited by 1 | Viewed by 1130
Abstract
Pathogenic CFTR variants cause cystic fibrosis (CF), and CF-related disorders (CF-RD), including bilateral aplasia of the vas deferens (CBAVD). The spectrum of clinical manifestations depends on the CFTR genotype. The frequency and spectrum of the CFTR variants vary between populations and clinical groups. [...] Read more.
Pathogenic CFTR variants cause cystic fibrosis (CF), and CF-related disorders (CF-RD), including bilateral aplasia of the vas deferens (CBAVD). The spectrum of clinical manifestations depends on the CFTR genotype. The frequency and spectrum of the CFTR variants vary between populations and clinical groups. CFTR variants and genotypes were analyzed in Russian men with CF (n = 546) and CBAVD syndrome (n = 125). Pathogenic variants were detected in 93.95% and 39.2% of the CF and CBAVD alleles, respectively. The most frequent c.1521_1523del (F508del; p.Phe508del) variant was found in 541 (49.5%) CF alleles. A total of 162 CFTR genotypes were revealed in CF patients, including 152 homozygous and 394 compound-heterozygous. The most common CF-genotype was F508del/F508del (24.9%). Other frequent CF-genotypes were F508del/3849+10kbC>T, F508del/CFTRdele2,3, and F508del/E92K. CF-causing variants and/or 5T allele were found in 88% of CBAVD patients: 5T/CFTRmut (48.0%), CFTRmut/N (17.6%), CFTRmut/CFTRmut (6.4%), 5T/5T (10.4%), 5T/N (5.6%) and N/N (12.0%), with the most common CBAVD-genotype being F508del/5T (29.6%). The allele frequencies of F508del, CFTRdele2,3 394delTT, and 3849+10kbC>T were significantly higher in CF patients. L138ins/L138ins, 2184insA/E92K, and L138ins/N genotypes were found in CBAVD, but not in CF patients. The results indicate certain differences in the frequency of some CFTR variants and genotypes in Russian CF and CBAVD patients. Full article
(This article belongs to the Special Issue Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases)
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15 pages, 1462 KiB  
Article
Clinical Consequences and Functional Impact of the Rare S737F CFTR Variant and Its Responsiveness to CFTR Modulators
by Vito Terlizzi, Emanuela Pesce, Valeria Capurro, Valeria Tomati, Mariateresa Lena, Cristina Pastorino, Renata Bocciardi, Federico Zara, Claudia Centrone, Giovanni Taccetti, Carlo Castellani and Nicoletta Pedemonte
Int. J. Mol. Sci. 2023, 24(7), 6576; https://doi.org/10.3390/ijms24076576 - 31 Mar 2023
Cited by 2 | Viewed by 1353
Abstract
S737F is a Cystic Fibrosis (CF) transmembrane conductance regulator (CFTR) missense variant. The aim of our study was to describe the clinical features of a cohort of individuals carrying this variant. In parallel, by exploiting ex vivo functional and molecular analyses on nasal [...] Read more.
S737F is a Cystic Fibrosis (CF) transmembrane conductance regulator (CFTR) missense variant. The aim of our study was to describe the clinical features of a cohort of individuals carrying this variant. In parallel, by exploiting ex vivo functional and molecular analyses on nasal epithelia derived from a subset of S737F carriers, we evaluated its functional impact on CFTR protein as well as its responsiveness to CFTR modulators. We retrospectively collected clinical data of all individuals bearing at least one S737F CFTR variant and followed at the CF Centre of Tuscany region (Italy). Nasal brushing was performed in cooperating individuals. At study end clinical data were available for 10 subjects (mean age: 14 years; range 1–44 years; 3 adult individuals). Five asymptomatic subjects had CF, 2 were CRMS/CFSPID and 3 had an inconclusive diagnosis. Ex vivo analysis on nasal epithelia demonstrated different levels of CF activity. In particular, epithelia derived from asymptomatic CF subjects and from one of the subjects with inconclusive diagnosis showed reduced CFTR activity that could be rescued by treatment with CFTR modulators. On the contrary, in the epithelia derived from the other two individuals with an inconclusive diagnosis, the CFTR-mediated current was similar to that observed in epithelia derived from healthy donors. In vitro functional and biochemical analysis on S737F-CFTR expressed in immortalized bronchial cells highlighted a modest impairment of the channel activity, that was improved by treatment with ivacaftor alone or in combination with tezacaftor/elexacaftor. Our study provide evidence towards the evaluation of CFTR function on ex vivo nasal epithelial cell models as a new assay to help clinicians to classify individuals, in presence of discordance between clinical picture, sweat test and genetic profile. Full article
(This article belongs to the Special Issue Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases)
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18 pages, 4044 KiB  
Article
The COPD-Associated Polymorphism Impairs the CFTR Function to Suppress Excessive IL-8 Production upon Environmental Pathogen Exposure
by Daichi Hinata, Ryosuke Fukuda and Tsukasa Okiyoneda
Int. J. Mol. Sci. 2023, 24(3), 2305; https://doi.org/10.3390/ijms24032305 - 24 Jan 2023
Cited by 2 | Viewed by 2361
Abstract
COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl− channel, which is invoked in COPD. Despite [...] Read more.
COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl− channel, which is invoked in COPD. Despite the increased incidence of CFTR polymorphism R75Q or M470V in COPD patients, the mechanism of how the CFTR variant affects COPD pathogenesis remains unclear. Here, we investigated the impact of CFTR polymorphisms (R75Q, M470V) on the CFTR function in airway epithelial cell models. While wild-type (WT) CFTR suppressed the proinflammatory cytokine production induced by COPD-related pathogens including pyocyanin (PYO), R75Q- or M470V-CFTR failed. Mechanistically, the R75Q- or M470V-CFTR fractional PM activity (FPMA) was significantly lower than WT-CFTR in the presence of PYO. Notably, the CF drug Trikafta corrected the PM expression of R75Q- or M470V-CFTR even upon PYO exposure and consequently suppressed the excessive IL-8 production. These results suggest that R75Q or M470V polymorphism impairs the CFTR function to suppress the excessive proinflammatory response to environmental pathogens associated with COPD. Moreover, Trikafta may be useful to prevent the COPD pathogenesis associated with acquired CFTR dysfunction. Full article
(This article belongs to the Special Issue Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases)
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16 pages, 3312 KiB  
Article
Elevated Levels of Toxic Bile Acids in Serum of Cystic Fibrosis Patients with CFTR Mutations Causing Pancreatic Insufficiency
by Harold Tabori, Jochen Schneider, Stefan Lüth, Carlos Zagoya, Anton Barucha, Thomas Lehmann, Eberhard Kauf, Astrid Barth and Jochen G. Mainz
Int. J. Mol. Sci. 2022, 23(20), 12436; https://doi.org/10.3390/ijms232012436 - 18 Oct 2022
Cited by 2 | Viewed by 2010
Abstract
Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about [...] Read more.
Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest. Full article
(This article belongs to the Special Issue Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases)
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15 pages, 4984 KiB  
Article
A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
by Keiko Ueno-Shuto, Shunsuke Kamei, Megumi Hayashi, Ayami Fukuyama, Yuji Uchida, Naofumi Tokutomi, Mary Ann Suico, Hirofumi Kai and Tsuyoshi Shuto
Int. J. Mol. Sci. 2022, 23(14), 7748; https://doi.org/10.3390/ijms23147748 - 13 Jul 2022
Cited by 1 | Viewed by 2875
Abstract
Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF [...] Read more.
Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation. Full article
(This article belongs to the Special Issue Molecular Pathology and Therapy on Cystic Fibrosis and CFTR-Related Diseases)
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