Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment

2011 ◽  
Vol 49 (8) ◽  
Author(s):  
Rossella Tomaiuolo ◽  
Marsia Fausto ◽  
Ausilia Elce ◽  
Ida Strina ◽  
Antonio Ranieri ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Reproductive Technology ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
High Detection Rate ◽  
High Detection ◽  
Cftr Mutations ◽  
Gene Scanning ◽  
Cystic Fibrosis Transmembrane ◽  
Assisted Reproductive Technology Treatment

AbstractAn increased frequency of (cystic fibrosis transmembrane conductance regulator)We sequenced theThe frequency ofAll subjects affected by obstructive or secretory azoospermia should undergo molecular analysis and counselling for CF using gene scanning which has a high detection rate and also reveals rare CFTR mutations. Molecular analysis seems to be less mandatory in other types of male/female infertility. Furthermore, we found that the

scholarly journals Preclinical Studies of a Rare CF-Causing Mutation in the Second Nucleotide Binding Domain (c.3700A>G) Show Robust Functional Rescue in Primary Nasal Cultures by Novel CFTR Modulators

2020 ◽  
Vol 10 (4) ◽  
pp. 209
Author(s):  
Onofrio Laselva ◽  
Jacqueline McCormack ◽  
Claire Bartlett ◽  
Wan Ip ◽  
Tarini N. A. Gunawardena ◽  
...  
Keyword(s):  
Hek293 Cells ◽  
Transmembrane Conductance Regulator ◽  
The Novel ◽  
Triple Combination ◽  
Nucleotide Binding Domain ◽  
Transmembrane Conductance ◽  
Rare Mutation ◽  
Cftr Mutations ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

The combination therapies ORKAMBITM and TRIKAFTATM are approved for people who have the F508del mutation on at least one allele. In this study we examine the effects of potentiator and corrector combinations on the rare mutation c.3700A>G. This mutation produces a cryptic splice site that deletes six amino acids in NBD2 (I1234-R1239del). Like F508del it causes protein misprocessing and reduced chloride channel function. We show that a novel cystic fibrosis transmembrane conductance regulator CFTR modulator triple combination (AC1, corrector, AC2-2, co-potentiator and AP2, potentiator), rescued I1234-R1239del-CFTR activity to WT-CFTR level in HEK293 cells. Moreover, we show that although the response to ORKAMBI was modest in nasal epithelial cells from two individuals homozygous for I1234-R1239del-CFTR, a substantial functional rescue was achieved with the novel triple combination. Interestingly, while both the novel CFTR triple combination and TRIKAFTATM treatment showed functional rescue in gene-edited I1234-R1239del-CFTR-expressing HBE cells and in nasal cells from two CF patients heterozygous for I1234-R1239del/W1282X, nasal cells homozygous for I1234-R1239del-CFTR showed no significant response to the TRIKAFTATM combination. These data suggest a potential benefit of CFTR modulators on the functional rescue of I1234-R1239del -CFTR, which arises from the rare CF-causing mutation c.3700A>G, and highlight that patient tissues are crucial to our full understanding of functional rescue in rare CFTR mutations.

scholarly journals Interleukin 8 Secretion from Monocytes of Subjects Heterozygous for the ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutation Is Altered

2004 ◽  
Vol 11 (5) ◽  
pp. 819-824 ◽  
Author(s):  
Munir M. Zaman ◽  
Andres Gelrud ◽  
Omer Junaidi ◽  
Meredith M. Regan ◽  
Michel Warny ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mapk Signaling ◽  
Receptor Expression ◽  
Interleukin 8 ◽  
Healthy Controls ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Surface Receptors ◽  
Cftr Mutations ◽  
Cystic Fibrosis Transmembrane

ABSTRACT Patients with cystic fibrosis (CF) exhibit an excessive host inflammatory response. The aim of this study was to determine (i) whether interleukin 8 (IL-8) secretion is increased from monocytes from subjects heterozygous as well as homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and (ii) whether this is due to increased cell surface lipopolysaccharide (LPS) receptors or, alternatively, increased activation of mitogen-activated protein kinases (MAPK). The basal level of IL-8 secretion was higher from monocytes from CF patients than from monocytes from healthy controls (P = 0.02) and obligate heterozygotes (parents of the CF patients). The 50% effective concentrations for LPS-induced IL-8 production for monocytes from both CF patients and obligate heterozygotes were 100-fold lower than those for monocytes from healthy controls (P < 0.05). No differences in the levels of IL-1β production were seen between these groups. Expression of the LPS surface receptors CD14 and Toll-like receptor 4 were not different between CF patients and healthy controls. In contrast, phosphorylation of the MAPKs p38 and ERK occurred at lower doses of LPS in monocytes from patients heterozygous and homozygous for CFTR mutations. These results indicate that a single allelic CFTR mutation is sufficient to augment IL-8 secretion in response to LPS. This is not a result of increased LPS receptor expression but, rather, is associated with alterations in MAPK signaling.

scholarly journals Molecular analysis of CFTR gene mutations among Iraqi cystic fibrosis patients

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Asal Gailan Abdul-Qadir ◽  
Bassam Musa Al-Musawi ◽  
Rabab Farhan Thejeal ◽  
Saad Abdul-Baqi Al-Omar
Keyword(s):  
Cystic Fibrosis ◽  
Molecular Analysis ◽  
Autosomal Recessive ◽  
Gene Mutations ◽  
Regional Studies ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Multisystem Disease ◽  
Polymorphic Variants ◽  
Cystic Fibrosis Transmembrane

Abstract Background Cystic fibrosis (CF) is an autosomal recessive multisystem disease that results from mutation(s) of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. More than 2100 mutations and polymorphisms have been reported in this gene so far. Incidence and genotyping of CF are under-identified in Iraq. This study aims to determine the types and frequencies of certain CFTR mutations among a sample of Iraqi CF patients. Two groups of patients were included: 31 clinically confirmed CF patients in addition to 47 clinically suspected patients of CF. All confirmed patients had typical, moderate-severe clinical presentation and course of the disease. Molecular analysis was performed on the majority of enrolled patients using the CF-stripAssay® kit supplied by ViennaLab diagnostics, GmbH, Austria. Results The mutation-detection rate from the tested 34 mutations in this study was 19.5% and the 8 detected mutations were as follows: 3120+1G>A and W1282X were found in 3 (4.17%) patients each; F508del and R1162X were found in 2 (2.78%) patients each; 3272-26A>G, R347P, I507del, and 2183AA>G were found in 1 (1.38%) patient each. Polymorphic variants of IVS8, namely 5T, 7T, and 9T, were detected in ~ 70%. These results were nearly similar to what was reported in regional countries. Conclusion Cystic fibrosis seems to be not rare as previously thought. 3120+1G>A and W1282X are the two most commonly detected mutations. F508del needs to be included in all future tests, while the I507del mutation was uniquely reported in this study but not in regional studies.

scholarly journals Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis

2013 ◽  
Vol 39 (2) ◽  
pp. 181-189 ◽  
Author(s):  
Vinícius Buaes Dal'Maso ◽  
Lucas Mallmann ◽  
Marina Siebert ◽  
Laura Simon ◽  
Maria Luiza Saraiva-Pereira ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Molecular Analysis ◽  
Clinical Characteristics ◽  
Genetic Diagnosis ◽  
Cftr Gene ◽  
Sweat Test ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

OBJECTIVE: To evaluate the diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suspected of having mild or atypical cystic fibrosis (CF). METHODS: This was a cross-sectional study involving adolescents and adults aged ≥ 14 years. Volunteers underwent clinical, laboratory, and radiological evaluation, as well as spirometry, sputum microbiology, liver ultrasound, sweat tests, and molecular analysis of the CFTR gene. We then divided the patients into three groups by the number of mutations identified (none, one, and two or more) and compared those groups in terms of their characteristics. RESULTS: We evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation. The mean age of the patients was 32.5 ± 13.6 years, and females predominated (75.7%). The molecular analysis contributed to the definitive diagnosis of CF in 3 patients (8.1%), all of whom had at least two mutations. There were 7 patients (18.9%) with only one mutation and 26 patients (70.3%) with no mutations. None of the clinical characteristics evaluated was found to be associated with the genetic diagnosis. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H, and p.T351S. CONCLUSIONS: The molecular analysis of the CFTR gene coding region showed a limited contribution to the diagnostic investigation of patients suspected of having mild or atypical CF. In addition, there were no associations between the clinical characteristics and the genetic diagnosis.

A functional CFTR-NBF1 is required for ROMK2-CFTR interaction

1997 ◽  
Vol 273 (5) ◽  
pp. F843-F848 ◽  
Author(s):  
Carmel M. McNicholas ◽  
Malcolm W. Nason ◽  
William B. Guggino ◽  
Erik M. Schwiebert ◽  
Steven C. Hebert ◽  
...  
Keyword(s):  
Xenopus Oocytes ◽  
Point Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Enhanced Sensitivity ◽  
Cftr Mutations ◽  
Cystic Fibrosis Transmembrane ◽  
Inwardly Rectifying ◽  
Inside Out

In a previous study on inside-out patches of Xenopus oocytes, we demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR) enhances the glibenclamide sensitivity of a coexpressed inwardly rectifying K+ channel, ROMK2 (C. M. McNicholas, W. B. Guggino, E. M. Schwiebert, S. C. Hebert, G. Giebisch, and M. E. Egan. Proc. Natl. Acad. Sci. USA 93: 8083–8088, 1996). In the present study, we used the two-microelectrode voltage-clamp technique to measure whole cell K+ currents in Xenopus oocytes, and we further characterized the enhanced sensitivity of ROMK2 to glibenclamide by CFTR. Glibenclamide inhibited K+currents by 56% in oocytes expressing both ROMK2 and CFTR but only 11% in oocytes expressing ROMK2 alone. To examine the role of the first nucleotide binding fold (NBF1) of CFTR in the ROMK2-CFTR interaction, we studied the glibenclamide sensitivity of ROMK2 when coexpressed with CFTR constructs containing mutations in or around the NBF1 domain. In oocytes coinjected with ROMK2 and a truncated construct of CFTR with an intact NBF1 (CFTR-K593X), glibenclamide inhibited K+ currents by 46%. However, in oocytes coinjected with ROMK2 and a CFTR mutant truncated immediately before NBF1 (CFTR-K370X), glibenclamide inhibited K+ currents by 12%. Also, oocytes expressing both ROMK2 and CFTR mutants with naturally occurring NBF1 point mutations, CFTR-G551D or CFTR-A455E, display glibenclamide-inhibitable K+currents of only 14 and 25%, respectively. Because CFTR mutations that alter the NBF1 domain reduce the glibenclamide sensitivity of the coexpressed ROMK2 channel, we conclude that the NBF1 motif is necessary for the CFTR-ROMK2 interaction that confers sulfonylurea sensitivity.

scholarly journals Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ciaran A. Shaughnessy ◽  
Pamela L. Zeitlin ◽  
Preston E. Bratcher
Keyword(s):  
Cystic Fibrosis ◽  
Early Death ◽  
New Combination ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Acute And Chronic Treatment ◽  
Cftr Mutations ◽  
Small Molecule Modulators ◽  
Cystic Fibrosis Transmembrane

AbstractCystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.

Diagnosis of cystic fibrosis in adulthood and eligibility for novel CFTR modulator therapy

2021 ◽  
pp. postgradmedj-2020-139278
Author(s):  
Hannah Farley ◽  
Sarah Poole ◽  
Stephen Chapman ◽  
William Flight
Keyword(s):  
Cystic Fibrosis ◽  
Chronic Respiratory Disease ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Radiological Data ◽  
Patient Database ◽  
Cftr Mutations ◽  
History Of ◽  
Autosomal Recessive Condition ◽  
Cystic Fibrosis Transmembrane

BackgroundCystic fibrosis (CF) is an autosomal recessive condition that primarily manifests as a chronic respiratory disease. CF is usually diagnosed in early childhood or through newborn screening although in a small but important group, diagnosis is not made until adulthood. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are now available for most genetic causes of CF highlighting the importance of identifying people with late presentations of CF.AimWe aimed to identify the clinical characteristics of people diagnosed with CF in adulthood and their resulting eligibility for novel CFTR modulator therapies.DesignRetrospective single-centre cohort study.MethodsPatients diagnosed with CF at age 18 years or older were identified from a patient database. Paper and electronic medical records were reviewed and clinical, microbiological and radiological data at diagnosis were recorded.ResultsNineteen patients were identified. Median age at diagnosis was 38 years (range: 19–71) and 9 (47%) were female. All patients had a history of chronic respiratory symptoms and 18/19 (94%) had radiological evidence of bronchiectasis. All patients had two pathogenic CFTR mutations identified with 16/19 (84%) compound heterozygotes for the F508del mutation. The majority of patients had a CFTR genotype considered eligible for CFTR modulator therapy (84% and 89% according to European and US licences, respectively).ConclusionsAdult patients with unexplained chronic bronchiectasis should be thoroughly investigated for CF. A low index of suspicion will help to identify adults with undiagnosed CF who are likely to benefit from CFTR modulator therapy.

scholarly journals Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations in a Cohort of Patients Residing in Palestine

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0133890 ◽  
Author(s):  
Issa Siryani ◽  
Mohamed Jama ◽  
Nisreen Rumman ◽  
Hiyam Marzouqa ◽  
Moein Kannan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cftr Mutations ◽  
Cystic Fibrosis Transmembrane
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