scholarly journals Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis

2015 ◽  
Vol 2015 ◽  
pp. 1-4
Author(s):  
Rossana Molinario ◽  
Sara Palumbo ◽  
Paola Concolino ◽  
Sandro Rocchetti ◽  
Roberta Rizza ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Incidental Finding ◽  
Pancreatic Insufficiency ◽  
Normal Male ◽  
Transmembrane Conductance Regulator ◽  
Coding Region ◽  
Multiple Organs ◽  
Rare Polymorphism ◽  
The Many ◽  
Next Generation Sequencing Ngs

Cystic fibrosis (CF; OMIM number 219700) is an autosomal recessive disease caused by mutations in theCFTR(cystic fibrosis transmembrane conductance regulator) gene, which results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency, chronic endobronchial infection, and male infertility. We report the case of a 47-year-old apparently normal male resulting in homozygosity for the mutation p.M348K from nonconsanguineous parents. The proband was screened using a standard panel of 70 different tested on NanoChip 400 platform. The massive parallel pyrosequencing on 454 JS machine allowed the second level analysis. The patient was firstly screened with two different platforms available in our laboratory, obtaining an ambiguous signal for the p.R347P mutation. For this reason we decided to clarify the discordant result ofCFTRstatus by Next Generation Sequencing (NGS) using 454 Junior instrument. The patient is resulted no carrier of the p.R347P mutation, but NGS highlighted a homozygous substitution from T>A at position 1043 in the coding region, causing an amino acid substitution from methionine to lysine (p.M348K). Casual finding of p.M348K homozygote mutation in an individual, without any feature of classical or nonclassical CF form, allowed us to confirm that p.M348K is a benign rare polymorphism.

scholarly journals Quantitative Evaluation of CFTR Pre-mRNA Splicing Dependent on the (TG)mTn Poly-Variant Tract

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 168
Author(s):  
Manuela Sterrantino ◽  
Andrea Fuso ◽  
Silvia Pierandrei ◽  
Sabina Maria Bruno ◽  
Giancarlo Testino ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Functional Effect ◽  
Transmembrane Conductance ◽  
Therapeutic Consequences ◽  
Clinical Consequences ◽  
Exon 9 ◽  
The Many ◽  
Cystic Fibrosis Transmembrane ◽  
Exon 10

Genetic analysis in cystic fibrosis (CF) is a difficult task. Within the many causes of variability and uncertainty, a major determinant is poor knowledge of the functional effect of most DNA variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. In turn, knowledge of the effect of a CFTR variant has dramatic diagnostic, prognostic and, in the era of CF precision medicine, also therapeutic consequences. One of the most challenging CFTR variants is the (TG)mTn haplotype, which has variable functional effect and controversial clinical consequences. The exact quantification of the anomalous splicing of CFTR exon 10 (in the HGVS name; exon 9 in the legacy name) and, consequently, of the residual wild-type functional CFTR mRNA, should be mandatory in clinical assessment of patients with potentially pathological haplotype of this tract. Here, we present a real time-based assay for the quantification of the proportion of exon 10+/exon 10− CFTR mRNA, starting from nasal brushing. Our assay proved rapid, economic and easy to perform. Specific primers used for this assay are either disclosed or commercially available, allowing any laboratory to easily perform it. A simplified analysis of the data is provided, facilitating the interpretation of the results. This method helps to enhance the comprehension of the genotype–phenotype relationship in CF and CFTR-related disorders (CFTR-RD), crucial for the diagnosis, prognosis and personalized therapy of CF.

scholarly journals Regulation of CFTR Biogenesis by the Proteostatic Network and Pharmacological Modulators

2020 ◽  
Vol 21 (2) ◽  
pp. 452 ◽  
Author(s):  
Samuel Estabrooks ◽  
Jeffrey L. Brodsky
Keyword(s):  
Cystic Fibrosis ◽  
Common Disease ◽  
Transmembrane Conductance Regulator ◽  
Inherited Disease ◽  
Transmembrane Conductance ◽  
Gene Encoding ◽  
The Many ◽  
And Function ◽  
Cystic Fibrosis Transmembrane ◽  
Pharmacological Modulators

Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians in North America and a significant portion of Europe. The disease arises from one of many mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator, or CFTR. The most common disease-associated allele, F508del, along with several other mutations affect the folding, transport, and stability of CFTR as it transits from the endoplasmic reticulum (ER) to the plasma membrane, where it functions primarily as a chloride channel. Early data demonstrated that F508del CFTR is selected for ER associated degradation (ERAD), a pathway in which misfolded proteins are recognized by ER-associated molecular chaperones, ubiquitinated, and delivered to the proteasome for degradation. Later studies showed that F508del CFTR that is rescued from ERAD and folds can alternatively be selected for enhanced endocytosis and lysosomal degradation. A number of other disease-causing mutations in CFTR also undergo these events. Fortunately, pharmacological modulators of CFTR biogenesis can repair CFTR, permitting its folding, escape from ERAD, and function at the cell surface. In this article, we review the many cellular checkpoints that monitor CFTR biogenesis, discuss the emergence of effective treatments for CF, and highlight future areas of research on the proteostatic control of CFTR.

scholarly journals Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis

2019 ◽  
Vol 08 (03) ◽  
pp. 147-152
Author(s):  
Flor Vásquez Sotomayor ◽  
Hugo Hernán Abarca-Barriga
Keyword(s):  
Cystic Fibrosis ◽  
Pancreatic Insufficiency ◽  
Chromosomal Rearrangements ◽  
Correct Diagnosis ◽  
Homozygous Deletion ◽  
Cftr Gene ◽  
Molecular Testing ◽  
Transmembrane Conductance Regulator ◽  
First Case ◽  
History Of

AbstractWe report the first case in Peru of cystic fibrosis caused by a homozygous deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A 10-month-old child who presented with meconium ileus and pancreatic insufficiency was tested for cystic fibrosis. Both parents of the child are of Peruvian background, are nonconsanguineous, and have no personal or family history of the disease. Chromosome microarray analysis revealed a homozygous deletion of the CFTR gene on chromosome 7 (7q31.2) within a maternally derived 12.8-Mb region of loss of heterozygosity with deletion of a region that includes the CFTR gene. Parental testing confirmed this finding. This case highlights the great importance of molecular testing and the study of chromosomal rearrangements in reaching a correct diagnosis and providing proper genetic counseling to the affected families.

scholarly journals Intestinal current measurement and nasal potential difference to make a diagnosis of cases with inconclusive CFTR genetics and sweat test

2020 ◽  
Vol 7 (1) ◽  
pp. e000736 ◽  
Author(s):  
Rebecca Minso ◽  
Angela Schulz ◽  
Christian Dopfer ◽  
Nadine Alfeis ◽  
Andrea van Barneveld ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Symptoms ◽  
Potential Difference ◽  
Sweat Test ◽  
Transmembrane Conductance Regulator ◽  
Coding Region ◽  
Transmembrane Conductance ◽  
Related Disorder ◽  
False Positive Diagnosis ◽  
Nasal Potential Difference

BackgroundNasal potential difference (NPD) and intestinal current measurements (ICM) are cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers recommended to make a diagnosis in individuals with inconclusive sweat test and CFTR genetics and a clinical suspicion for cystic fibrosis (CF) or CFTR-related disorder (CFTR-RD).MethodsNPD and ICM were measured according to standard operating procedures of the European Cystic Fibrosis Society Diagnostic Network Working Group.ResultsWe assessed 219 individuals by NPD or ICM who had been referred to our laboratory due to clinical symptoms suggestive of CF, but inconclusive sweat test and CFTR genetics (median age: 16.3 years, range 0.4 to 76 years). CF or CFTR-related disorder was diagnosed in 22 of 29 patients (76%) with a CFTR genotype of unknown or variable clinical significance and in 51 of 190 carriers (27%) of one (35/42) or no (16/148) identified CFTR mutation. If two CFTR sequence variants had been identified, the outcome of NPD and ICM was consistent with the classification of the CFTR2 database. Moreover, a suspected false-positive diagnosis of CF was confirmed in seven and withdrawn in eight patients. Of 26 individuals assessed by both NPD and ICM, eleven individuals exhibited discordant tracings of ICM and NPD, with one measurement being in the CF range and the other in the normal range.ConclusionThe majority of patients whom we diagnosed with CF or CFTR-RD by extended electrophysiology are carriers of the wild-type CFTR coding sequence on at least one of their CF alleles. The disease-causing genetic lesions should reside in the non-coding region of CFTR or elsewhere in the genome, affecting the regulation of CFTR expression in a tissue-depending fashion which may explain the large within-group variability of CFTR activity in the respiratory and intestinal epithelium seen in this group.

scholarly journals Sustained Glycemic Control With Ivacaftor in Cystic Fibrosis–Related Diabetes

2019 ◽  
Vol 7 ◽  
pp. 232470961984289 ◽  
Author(s):  
Francis Christian ◽  
Andrew Thierman ◽  
Erin Shirley ◽  
Karen Allen ◽  
Cory Cross ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Secretion ◽  
Glycemic Control ◽  
Pancreatic Insufficiency ◽  
Disease Process ◽  
Current Treatment ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Endogenous Insulin ◽  
Short Period

Cystic fibrosis–related diabetes (CFRD) is a common comorbidity in cystic fibrosis with pancreatic insufficiency occurring early in the disease process. Current treatment is exogenous insulin therapy as CFRD is due to impaired insulin secretion. Recent small studies have shown improvement in endogenous insulin secretion with a short period of ivacaftor therapy in primarily pediatric patients with cystic fibrosis transmembrane conductance regulator mutations amenable to potentiation. In this article, we present the case of an adult patient with long-standing CFRD who developed sustained improvement in glycemic control after initiation of ivacaftor.

scholarly journals Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

2008 ◽  
Vol 42 (4) ◽  
pp. 389-412 ◽  
Author(s):  
I Kukavica-Ibrulj ◽  
R C Levesque
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Animal Models ◽  
Pancreatic Insufficiency ◽  
Lung Infection ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Human Form ◽  
Cftr Protein ◽  
Chronic Lung Infection

Summary Cystic fibrosis (CF) is caused by a defect in the transmembrane conductance regulator (CFTR) protein that functions as a chloride channel. Dysfunction of the CFTR protein results in salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility and severe pulmonary disease. In most patients with CF life expectancy is limited due to a progressive loss of functional lung tissue. Early in life a persistent neutrophylic inflammation can be demonstrated in the airways. The cause of this inflammation, the role of CFTR and the cause of lung morbidity by different CF-specific bacteria, mostly Pseudomonas aeruginosa, are not well understood. The lack of an appropriate animal model with multi-organ pathology having the characteristics of the human form of CF has hampered our understanding of the pathobiology and chronic lung infections of the disease for many years. This review summarizes the main characteristics of CF and focuses on several available animal models that have been frequently used in CF research. A better understanding of the chronic lung infection caused particularly by P. aeruginosa, the pathophysiology of lung inflammation and the pathogenesis of lung disease necessitates animal models to understand CF, and to develop and improve treatment.

scholarly journals The Microbiome in Cystic Fibrosis Pulmonary Disease

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 536 ◽  
Author(s):  
Alice Françoise ◽  
Geneviève Héry-Arnaud
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Status ◽  
Clinical Manifestations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Microbial World ◽  
Complementary Approach ◽  
Genome Interactions ◽  
Next Generation Sequencing Ngs ◽  
Microbiome Data

Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher.

scholarly journals Cell-Based Therapeutic Approaches for Cystic Fibrosis

2020 ◽  
Vol 21 (15) ◽  
pp. 5219
Author(s):  
Pascal Duchesneau ◽  
Thomas K. Waddell ◽  
Golnaz Karoubi
Keyword(s):  
Cystic Fibrosis ◽  
Cell Therapy ◽  
Treatment Method ◽  
Transmembrane Conductance Regulator ◽  
Therapeutic Approaches ◽  
Ips Cell ◽  
Multiple Organs ◽  
Current State ◽  
Cell Sources ◽  
Induced Pluripotent

Cystic Fibrosis (CF) is a chronic autosomal recessive disease caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic Fibrosis affects multiple organs but progressive remodeling of the airways, mucus accumulation, and chronic inflammation in the lung, result in lung disease as the major cause of morbidity and mortality. While advances in management of CF symptoms have increased the life expectancy of this devastating disease, and there is tremendous excitement about the potential of new agents targeting the CFTR molecule itself, there is still no curative treatment. With the recent advances in the identification of endogenous airway progenitor cells and in directed differentiation of pluripotent cell sources, cell-based therapeutic approaches for CF have become a plausible treatment method with the potential to ultimately cure the disease. In this review, we highlight the current state of cell therapy in the CF field focusing on the relevant autologous and allogeneic cell populations under investigation and the challenges associated with their use. In addition, we present advances in induced pluripotent stem (iPS) cell approaches and emerging new genetic engineering methods, which have the capacity to overcome the current limitations hindering cell therapy approaches.

Drug Optimization for Cystic Fibrosis Patients Based on Disease Pathways Crosstalk

2021 ◽  
Vol 11 (1) ◽  
pp. 1-11
Author(s):  
Shuting Lin ◽  
Yifei Wang
Keyword(s):  
Cystic Fibrosis ◽  
Pancreatic Insufficiency ◽  
Cftr Gene ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Dna Mutations ◽  
Pathway Crosstalk ◽  
Disease Modifier ◽  
Drug Optimization ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a common autosomal recessive disease characterized by pancreatic insufficiency and progressive deterioration of lung function. It has been shown that CF is caused by the presence of mutations in both alleles at the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The severity of CF disease reflects the change of molecular mechanism, including DNA mutations on CFTR gene and polymorphic variations in disease modifier genes. Better understanding the differences among different CF severity group is helpful for improving therapeutic plans for patients. In this paper, the authors present a computational network biology approach to screen precision drugs for CF patients, which is based on the intensity of drugs impact on the pathway crosstalk mediated by differential methylation genes. The results indicate that ivacaftor, tezacaftor, and lumacaftor are applicable to all severity cohorts, gefitinib, sorafenib, sunitinib, and imatinib mesylate have the potential to treat intermediary CF patients, and tamoxifen may be useful to mild and sever CF patients.

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