scholarly journals TMEM16A/ANO1: Current Strategies and Novel Drug Approaches for Cystic Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2867
Author(s):  
Christie Mitri ◽  
Himanshu Sharma ◽  
Harriet Corvol ◽  
Olivier Tabary
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channel ◽  
Complex Disease ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Hereditary Diseases ◽  
Specific Gene ◽  
Anoctamin 1 ◽  
Cf Transmembrane Conductance Regulator ◽  
Novel Drug

Cystic fibrosis (CF) is the most common of rare hereditary diseases in Caucasians, and it is estimated to affect 75,000 patients globally. CF is a complex disease due to the multiplicity of mutations found in the CF transmembrane conductance regulator (CFTR) gene causing the CFTR protein to become dysfunctional. Correctors and potentiators have demonstrated good clinical outcomes for patients with specific gene mutations; however, there are still patients for whom those treatments are not suitable and require alternative CFTR-independent strategies. Although CFTR is the main chloride channel in the lungs, others could, e.g., anoctamin-1 (ANO1 or TMEM16A), compensate for the deficiency of CFTR. This review summarizes the current knowledge on calcium-activated chloride channel (CaCC) ANO1 and presents ANO1 as an exciting target in CF.

scholarly journals Structure and Function of the CFTR Chloride Channel

1999 ◽  
Vol 79 (1) ◽  
pp. S23-S45 ◽  
Author(s):  
DAVID N. SHEPPARD ◽  
MICHAEL J. WELSH
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channel ◽  
Atp Hydrolysis ◽  
Current Knowledge ◽  
Structure And Function ◽  
Binding Domains ◽  
Transporter Family ◽  
Membrane Spanning ◽  
And Function ◽  
R Domain

Sheppard, David N., and Michael J. Welsh. Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79 , Suppl.: S23–S45, 1999. — The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl− channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.

Current Challenges in Cystic Fibrosis Screening

2003 ◽  
Vol 127 (9) ◽  
pp. 1133-1139 ◽  
Author(s):  
Elaine Lyon ◽  
Christine Miller
Keyword(s):  
Cystic Fibrosis ◽  
Health Care Providers ◽  
Patient Information ◽  
Phenotypic Expression ◽  
Gene Mutations ◽  
Care Providers ◽  
Idiopathic Pancreatitis ◽  
Advantages And Disadvantages ◽  
Bilateral Absence ◽  
Cf Transmembrane Conductance Regulator

Abstract Content.—This article gives an overview of the symptoms and mutations associated with classic and atypical cystic fibrosis (CF). Current testing methods for mutation detection in CF are discussed. Objectives.—Review testing for CF, including American College of Medical Genetics and American College of Obstetrics and Gynecology guidelines and recommendations regarding population screening for CF. Describe symptomatic and mutational differences between patients with classic CF and atypical CF, including monosymptomatic conditions such as congenital bilateral absence of the vas deferens, idiopathic pancreatitis, and chronic sinusitis. Explain the concern about predicting the phenotypic expression of the condition from the genotype. Discuss the challenges of CF testing, including the preanalytic, analytic, and postanalytic phases. List the current methods for detecting CF transmembrane conductance regulator gene mutations, specifying the advantages and disadvantages of each. Describe the basic patient information necessary for laboratories to provide accurate risk assessments, such as ethnicity and family history, and reasons for the test being conducted (carrier or affected status). Results.—The technical challenges of detecting the 25 recommended mutations are being met by commercially available reagents. Challenges remain for the preanalytic and postanalytic phases. Only with accurate patient information can laboratories provide specific risk reductions on the basis of a negative genetic test result. Conclusion.—As health care providers become better informed about the recommendations for CF testing and laboratories continue to increase the sensitivities of their assays, patients will benefit from increased screening efficiency and accuracy. This will allow affected individuals to receive prompt and effective treatment and carriers to enjoy an expanded number of reproductive options.

Screening of Specific Gene Mutations Associated with Cystic Fibrosis

2014 ◽  
Vol 26 (6) ◽  
pp. 1362-1372 ◽  
Author(s):  
Tania García-Mendiola ◽  
Tegra Barreiro Martínez ◽  
Félix Pariente ◽  
Jesús Molano ◽  
Encarnación Lorenzo
Keyword(s):  
Cystic Fibrosis ◽  
Gene Mutations ◽  
Specific Gene

scholarly journals Hypertonic saline in people with cystic fibrosis: review of comparative studies and clinical practice

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Vito Terlizzi ◽  
Eleonora Masi ◽  
Michela Francalanci ◽  
Giovanni Taccetti ◽  
Diletta Innocenti
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Hypertonic Saline ◽  
Current Knowledge ◽  
Lung Damage ◽  
Average Life Expectancy ◽  
Multisystem Disorder ◽  
Cf Transmembrane Conductance Regulator ◽  
The Individual ◽  
Mucolytic Agents

AbstractCystic fibrosis (CF) is a multisystem disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. These cause a reduced secretion of chloride, a marked absorption of sodium and, therefore, of water, through the epithelium, resulting in the formation of thickened secretions in organs such as lung or pancreas. These viscous secretions lead to airway obstruction, chronic infection and inflammation resulting in progressive lung damage, bronchiectasis and eventual respiratory failure. Although the average life expectancy has increased over the last 30 years, lung disease is the most common cause of death in people with CF. For these reasons, the improvement of sputum clearance is a major therapeutic aim in CF and early initiation of airway clearance is widely recommended and implemented. Symptomatic mucolytic therapy today is mainly based on inhalation of DNase, hypertonic saline or mannitol, in combination with physiotherapy. Mucolytic agents break down the gel structure of mucus and therefore decrease its elasticity and viscosity, reducing the pulmonary exacerbation frequency and to improve and stabilize lung function. Nevertheless, high quality studies comparing these mucolytic drugs are still few, and the individual experiences of patients and caregivers explain the high variability of their use globally. This review will summarize the current knowledge on hypertonic saline in the treatment of CF lung disease. Furthermore, we report the real-world prescription of inhaled mucolytic agents in CF.

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

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 670
Author(s):  
Chadia Mekki ◽  
Abdel Aissat ◽  
Véronique Mirlesse ◽  
Sophie Mayer Lacrosniere ◽  
Elsa Eche ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Mutations ◽  
Cftr Gene ◽  
Intestinal Loop ◽  
Fetal Ultrasound ◽  
Pathogenic Variants ◽  
Frequent Mutations ◽  
Multiethnic Population ◽  
Exhaustive Study ◽  
Cf Transmembrane Conductance Regulator

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.

Identification of Antineoplastic Targets with Systems Approaches, Using Resveratrol as an In-Depth Case Study

2017 ◽  
Vol 23 (32) ◽  
pp. 4773-4793 ◽  
Author(s):  
Nivedita Singh ◽  
Sherry Freiesleben ◽  
Olaf Wolkenhauer ◽  
Yogeshwer Shukla ◽  
Shailendra K. Gupta
Keyword(s):  
Drug Target ◽  
Complex Disease ◽  
Biological Targets ◽  
Systems Approaches ◽  
Anticancer Mechanism ◽  
Genetic And Environmental Factors ◽  
Key Steps ◽  
Network Approaches ◽  
Novel Drug

The identification and validation of novel drug–target combinations are key steps in the drug discovery processes. Cancer is a complex disease that involves several genetic and environmental factors. High-throughput omics technologies are now widely available, however the integration of multi-omics data to identify viable anticancer drug-target combinations, that allow for a better clinical outcome when considering the efficacy-toxicity spectrum, is challenging. This review article provides an overview of systems approaches which help to integrate a broad spectrum of technologies and data. We focus on network approaches and investigate anticancer mechanism and biological targets of resveratrol using reverse pharmacophore mapping as an in-depth case study. The results of this case study demonstrate the use of systems approaches for a better understanding of the behavior of small molecule inhibitors in receptor binding sites. The presented network analysis approach helps in formulating hypotheses and provides mechanistic insights of resveratrol in neoplastic transformations.

scholarly journals The identification of novel gene mutations for degenerative lumbar spinal stenosis using whole-exome sequencing in a Chinese cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Jiang ◽  
Dong Chen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spinal Stenosis ◽  
Lumbar Spinal Stenosis ◽  
Gene Mutations ◽  
Specific Gene ◽  
Single Nucleotide ◽  
Degenerative Lumbar Spinal Stenosis ◽  
Whole Exome ◽  
Lumbar Spinal

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common lumbar disease that requires surgery. Previous studies have indicated that genetic mutations are implicated in DLSS. However, studies on specific gene mutations are scarce. Whole-exome sequencing (WES) is a valuable research tool that identifies disease-causing genes and could become an effective strategy to investigate DLSS pathogenesis. Methods From January 2016 to December 2017, we recruited 50 unrelated patients with symptoms consistent with DLSS and 25 unrelated healthy controls. We conducted WES and exome data analysis to identify susceptible genes. Allele mutations firstly identified potential DLSS variants in controls to the patients’ group. We conducted a site-based association analysis to identify pathogenic variants using PolyPhen2, SIFT, Mutation Taster, Combined Annotation Dependent Depletion, and Phenolyzer algorithms. Potential variants were further confirmed using manual curation and validated using Sanger sequencing. Results In this cohort, the major classification variant was missense_mutation, the major variant type was single nucleotide polymorphism (SNP), and the major single nucleotide variation was C > T. Multiple SNPs in 34 genes were identified when filtered allele mutations in controls to retain only patient mutations. Pathway enrichment analyses revealed that mutated genes were mainly enriched for immune response-related signaling pathways. Using the Novegene database, site-based associations revealed several novel variants, including HLA-DRB1, PARK2, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 genes, etc., were DLSS related. Conclusions Our study revealed that deleterious mutations in several genes might contribute to DLSS etiology. By screening and confirming susceptibility genes using WES, we provided more information on disease pathogenesis. Further WES studies incorporating larger DLSS patient cohorts are required to comprehend the genetic landscape of DLSS pathophysiology fully.

scholarly journals The substituted benzimidazolone NS004 is an opener of the cystic fibrosis chloride channel

1994 ◽  
Vol 269 (15) ◽  
pp. 10983-10986
Author(s):  
V.K. Gribkoff ◽  
G. Champigny ◽  
P. Barbry ◽  
S.I. Dworetzky ◽  
N.A. Meanwell ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channel

scholarly journals The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1102
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Valeria Raia ◽  
Guido Kroemer ◽  
Maria Chiara Maiuri
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Predictive Biomarkers ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

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