scholarly journals Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants

2016 ◽  
pp. 33 ◽  
Author(s):  
Karen Sánchez ◽  
Elizabeth De Mendonca ◽  
Xiorama Matute ◽  
Ismenia Chaustre ◽  
Marlene Villalon ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Cftr Gene

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Pancreatic Insufficiency ◽  
Protein Energy Malnutrition ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Missense Variants ◽  
Pathogenic Variants

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

scholarly journals Features of spectrum of pathogenic genetic variants of the CFTR gene in patients with cystic fibrosis from Krasnoyarsk territory

2020 ◽  
Vol 15 (2) ◽  
Author(s):  
Natalia Anatolievna Ilyenkova ◽  
Vladimir Viktorovich Chikunov ◽  
Elena Ivanovna Kondratieva
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Cftr Gene

scholarly journals CFTR F508del mutation and 5T allele in patients with chronic pancreatitis and pancreatic adenocarcinoma

2011 ◽  
Vol 58 (3) ◽  
pp. 43-47
Author(s):  
Aleksandra Nikolic ◽  
Jelena Dinic ◽  
Dragica Radojkovic ◽  
Snezana Lukic ◽  
Dragan Popovic ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chronic Pancreatitis ◽  
Pancreatic Adenocarcinoma ◽  
Genetic Variants ◽  
Cftr Gene ◽  
Common Mutation ◽  
Healthy Individuals ◽  
Pancreatic Diseases ◽  
Pancreatic Disorders ◽  
Pancreatic Pathology

Introduction: Mutations in the CFTR gene may be associated with various types of pancreatic pathology and result in higher risk of pancreatic disorders. While delta F508 is the most common mutation in cystic fibrosis patients, the allel 5T is associated with atypical forms of cystic fibrosis. Study aim: The aim of this study was to establish the frequencies of F508del mutation and 5T allele in the CFTR gene in patients with chronic pancreatitis and pancreatic cancer, as well as to investigate whether these genetic variants represent risk factors for pancreatic diseases. Study methods: The study has encompassed 50 patients with chronic pancreatitis and 50 patients with pancreatic adenocarcinoma, as well as 124 healthy individuals. The analysis of F508del mutation and alleles 5T, 7T and 9T of the polythymidine tract was performed on DNA extracted from periferal blood by PCR-mediated site-direted mutagenesis (PSM) method. Results: The frequency of F508del mutation in the group of patients with chronic pancreatitis (3.0%) was significantly increased (p=0.032) in comparison to the group of healthy individuals (0.4%), while other analyzed differences were not statistically significant. Conclusion: The results of this study indicate that F508del mutation in the CFTR gene respresents a risk factor for the development of chronic pancreatitis.

scholarly journals Variety of large rearrangements in the CFTR gene in Russian patients with Cystic Fibrosis

2020 ◽  
pp. 28-34
Author(s):  
Е.И. Кондратьева ◽  
Н.В. Петрова ◽  
А.Ю. Воронкова ◽  
С.А. Красовский ◽  
Е.Л. Амелина ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Russian Federation ◽  
Genetic Variants ◽  
Genetic Variant ◽  
Cftr Gene ◽  
Pathogenic Variants ◽  
The Russian Federation ◽  
Basic Characteristics ◽  
Gland Function ◽  
Large Rearrangements

Целью исследования стал анализ частоты протяженных перестроек гена CFTR и клинико-лабораторных характеристик пациентов с протяженными перестройками гена CFTR. В Регистр больных муковисцидозом РФ 2017 г. включены данные 3096 пациентов из 81 региона РФ, у которых выявлено 196 патогенных вариантов гена CFTR. Патогенные варианты обнаруживаются как в кодирующих, так и в интронных областях, и в регуляторных регионах гена CFTR. В гене CFTR относительно мало (около 2,5%) протяженных перестроек, но среди мутантных хромосом, в которых генетические варианты не были идентифицированы стандартными методами, такие перестройки составляют до 20%. По данным Регистра 2017 г. выявлен 21 пациент, несущий в своем генотипе крупные перестройки. Перестройки CFTRdele12,13del16, CFTRdele19-22(17а-19), CFTRdele8(7*), CFTRdele2-8(2-7*) ранее не были описаны в международных базах данных. Клиническая характеристика больных с протяженными перестройками не отличалась по основным признакам от пациентов с «тяжелыми» генотипами. Наличие в генотипе пациентов с протяженными перестройками варианта нуклеотидной последовательности гена CFTR, определяющего сохранную функцию поджелудочной железы, обусловило отсутствие у них панкреатической недостаточности. The aim of the study was to analyze large rearrangements in the CFTR gene in patients with cystic fibrosis in the Russian Federation in 2017. The Cystic Fibrosis Patients Registry of the Russian Federation for 2017 includes data from 3096 patients from 81 regions of the Russian Federation. To date, more than 2,000 mutations or variants of the nucleotide sequence of the CFTR gene have been described. In the Cystic Fibrosis Patients Registry of the Russian Federation for 2017, 196 pathogenic CFTR variants are given. Pathogenic variants are found both in the coding and in the intron regions, and in the regulatory regions of the CFTR gene. The CFTR gene has relatively few (about 2.5%) large rearrangements, but among mutant chromosomes in which genetic variants were not identified by standard methods, such rearrangements account for up to 20%. According to the Registry of 2017, 21 patients were identified that carried large rearrangements in their genotype. The rearrangements CFTRdele12,13del16, CFTRdele19-22 (17a-19), CFTRdele8 (7*), CFTRdele2-8 (2-7*) are not described in international databases. The clinical characteristics of patients with extensive rearrangements in the genotype did not differ in basic characteristics from patients with “severe” genotypes. The presence of a genetic variant in the genotype that determines the preserved function of the pancreas leads to the preservation of gland function in patients with large rearrangements in the genotype.

scholarly journals CFTR Cooperative Cis-Regulatory Elements in Intestinal Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2599
Author(s):  
Mégane Collobert ◽  
Ozvan Bocher ◽  
Anaïs Le Nabec ◽  
Emmanuelle Génin ◽  
Claude Férec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Gene Regulation ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Cftr Gene ◽  
Intestinal Cells ◽  
Cooperative Effects ◽  
Cis Acting ◽  
Study Techniques

About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator (CFTR) regulatory elements were identified, but the regulatory mechanisms of the CFTR gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the CFTR gene regulation, and to identity factors that could impact the CFTR gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as CFTR-related disorders. Here, we apply the robust GWAS3D score to determine which of the CFTR introns could be involved in gene regulation. This approach highlights four particular CFTR introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the CFTR gene regulation and allow us to suggest a 3D CFTR locus structure in intestinal cells. A better understand of regulation mechanisms of the CFTR gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These cis-acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future.

scholarly journals A Peptide-Nucleic Acid Targeting miR-335-5p Enhances Expression of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene with the Possible Involvement of the CFTR Scaffolding Protein NHERF1

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 117
Author(s):  
Anna Tamanini ◽  
Enrica Fabbri ◽  
Tiziana Jakova ◽  
Jessica Gasparello ◽  
Alex Manicardi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Nucleic Acid ◽  
Peptide Nucleic Acid ◽  
Stop Codon ◽  
Scaffolding Protein ◽  
Cftr Gene ◽  
Scaffolding Proteins ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

(1) Background: Up-regulation of the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) might be of great relevance for the development of therapeutic protocols for cystic fibrosis (CF). MicroRNAs are deeply involved in the regulation of CFTR and scaffolding proteins (such as NHERF1, NHERF2 and Ezrin). (2) Methods: Content of miRNAs and mRNAs was analyzed by RT-qPCR, while the CFTR and NHERF1 production was analyzed by Western blotting. (3) Results: The results here described show that the CFTR scaffolding protein NHERF1 can be up-regulated in bronchial epithelial Calu-3 cells by a peptide-nucleic acid (PNA) targeting miR-335-5p, predicted to bind to the 3′-UTR sequence of the NHERF1 mRNA. Treatment of Calu-3 cells with this PNA (R8-PNA-a335) causes also up-regulation of CFTR. (4) Conclusions: We propose miR-335-5p targeting as a strategy to increase CFTR. While the efficiency of PNA-based targeting of miR-335-5p should be verified as a therapeutic strategy in CF caused by stop-codon mutation of the CFTR gene, this approach might give appreciable results in CF cells carrying other mutations impairing the processing or stability of CFTR protein, supporting its application in personalized therapy for precision medicine.

scholarly journals High lysosomal activities in cystic fibrosis tracheal gland cells corrected by adenovirus-mediated CFTR gene transfer

1999 ◽  
Vol 1453 (1) ◽  
pp. 14-22 ◽  
Author(s):  
W. Kammouni ◽  
D. Naı̈mi ◽  
W. Renaud ◽  
N. Bianco ◽  
C. Figarella ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Transfer ◽  
Cftr Gene ◽  
Gland Cells

A Frequent Large Rearrangement in the CFTR Gene in Cystic Fibrosis Patients from Reunion Island

2006 ◽  
Vol 10 (3) ◽  
pp. 208-214 ◽  
Author(s):  
Juliette Nectoux ◽  
Marie Pierre Audrezet ◽  
Marion Viel ◽  
Chrystel Leroy ◽  
Odile Raguenes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cftr Gene ◽  
Reunion Island ◽  
Large Rearrangement ◽  
Réunion Island

Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment

2021 ◽  
Author(s):  
Karen S Raraigh ◽  
Melis A Aksit ◽  
Kurt Hetrick ◽  
Rhonda G Pace ◽  
Hua Ling ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Specific Treatment ◽  
Gene Sequencing ◽  
Cftr Gene
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