Clinical and genetic characterization of patients with cystic fibrosis and functional assessment of the chloride channel with the pathogenic variant c.831G&gt;A (p.Trp277*), described for the first time

Kondratyeva, E.I.; Ефремова, А.; Melyanovskaya, Y.; Петрова, Н. В.; Satsuk, N.; Bulatenko, N.; Бухарова, Т. Б.; Zodbinova, A.; Sherman, V.D.; Kashirskaya, N.; Зинченко, Р. А.; Kutsev, Sergey I.; Goldshtein, D. V.

doi:10.1016/j.gene.2020.145023

Cited by 7 publications

(9 citation statements)

References 14 publications

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“…The methods of obtaining stable cultures of intestinal organoids and the FIS assay were previously described in detail in studies by E. Kondratyeva (2020) and E. Kondratyeva (2021) [ 35 , 36 ]. The methods was based on protocols developed by J. M. Beekman’s guidance [ 20 , 37 , 38 ].…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy

Kondratyeva

Ефремова

Melyanovskaya

et al. 2022

IJMS

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In the cohort of Russian patients with cystic fibrosis, the p.[Leu467Phe;Phe508del] complex allele (legacy name [L467F;F508del]) of the CFTR gene is understudied. In this research, we present the results of frequency evaluation of the [L467F;F508del] complex allele in the Russian Federation among patients with a F508del/F508del genotype, its effect on the clinical course of cystic fibrosis, the intestinal epithelium ionic channel function, and the effectiveness of target therapy. The frequency of the [L467F;F508del] complex allele among patients with homozygous F508del was determined with multiplex ligase-dependent probe amplification followed by polymerase chain reaction and fragment analysis. The function of ionic channels, including the residual CFTR function, and the effectiveness of CFTR modulators was analyzed using intestinal current measurements on rectal biopsy samples and the forskolin-induced swelling assay on organoids. The results showed that the F508del/[L467F;F508del] genotype is present in 8.2% of all Russian patients with F508del in a homozygous state. The clinical course of the disease in patients with the F508del/[L467F;F508del] genotype is severe and does not vary from the course in the cohort with homozygous F508del, although the CFTR channel function is significantly lower. For patients with the F508del/[L467F;F508del] genotype, we can recommend targeted therapy using a combined ivacaftor + tezacaftor + elexacaftor medication.

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Section: Methodsmentioning

confidence: 99%

Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy

Kondratyeva

Ефремова

Melyanovskaya

et al. 2022

IJMS

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“…As a control were used two organoid cultures of CF-patient with F508del/F508del genotype and two organoid cultures of non-CF individuals [ 8 ].…”

Section: Methodsmentioning

confidence: 99%

“…This case also demonstrates the use of modern functional methods for assessing the function of the chloride channel—the determination of intestinal current measurement (ICM) and using a forskolin-induced swelling assay on intestinal organoids to assess the effectiveness of CFTR modulators. These methods have been used in the Russian Federation since 2018 at the Research Centre for Medical Genetics to study the pathogenicity of CFTR gene mutations not described in international databases in complex diagnostic cases, as well as to evaluate the effectiveness of targeted therapy for carriers of rare pathogenic variants [ 7 , 8 , 9 ]. Forskolin-induced swelling (FIS) assay of patient-derived organoids has been used to assessment of residual functional activity of the CFTR protein and to study the effects of CFTR modulators.…”

Section: Introductionmentioning

confidence: 99%

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Personalized Selection of a CFTR Modulator for a Patient with a Complex Allele [L467F;F508del]

Kondratyeva

Bulatenko

Melyanovskaya

et al. 2022

CIMB

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The presence of complex alleles in the CFTR gene can lead to difficulties in diagnosing cystic fibrosis and cause resistance to therapy with CFTR modulators. Tezacaftor/ivacaftor therapy for 8 months in a patient with the initially established F508del/F508del genotype did not lead to an improvement in her condition—there was no change in spirometry and an increase in the patient’s weight, while there was only a slight decrease in NaCl values, measured by a sweat test. The intestinal current measurements of the patient’s rectal biopsy showed no positive dynamics in the rescue of CFTR function while taking tezacaftor/ivacaftor. The assumption that the patient had an additional mutation in the cis position was confirmed by sequencing the CFTR gene, and the complex allele [L467F;F508del] was identified. Based on the rescue of CFTR function by elexacaftor/tezacaftor/ivacaftor obtained using forskolin-induced swelling on intestinal organoids, the patient was prescribed therapy with this targeted drug. The use of elexacaftor/tezacaftor/ivacaftor for 7 months resulted in a significant improvement in the patient’s clinical condition.

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“…Numerous studies of the last decade have demonstrated the dependence of the immune response on allelic polymorphism of cytokine genes. The result of such works in vitro is the identifi cation of individual alleles of genes associated with increased or decreased production of the corresponding cytokine [9]. The data obtained to date suggest that polymorphic cytokine genes are able to take an active part in the formation of a specifi c immune response to pathological conditions in humans [10].…”

Section: Introductionmentioning

confidence: 99%

Frequency Analysis Results Distribution of C589t Rs2243250 Polymorphism in Il4 Gene Among Patients with Chronic Rhinosinusitis

Ja¹,

Us²,

Un³

et al. 2021

J Biomed Res Environ Sci

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The fairly widespread prevalence of CRSwNP along with the lack of remedies for curing the disease, a variety of hypotheses of etiology dictate the need for further study of all links in the pathogenesis and clinical features of the course of the disease. In the coming century of “biological medicine”, the availability of high technologies of medical genetics makes it possible to reveal the individual characteristics of the most important regulatory systems of the body, which opens up new prospects for studying the etiology and pathogenesis of CRSwNP. In the tissues of polyps and intranasal secretions, an increase in the concentration of various inflammatory mediators, in particular interleukins, is observed due to an increase in their de novo synthesis by effector cells. Particular importance is attached to an increase in the concentration of cytokines involved in the development, recruitment and activation of eosinophils (IL-4, IL-12, IL-13, GM-CSF), the main pro-inflammatory (IL-1, IL-2, TNF-a, IL- 10), regulatory cytokines (IL-10, TLR2B), contributing to the chronicity of the inflammatory process in the nasal cavity.

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Clinical and genetic characterization of patients with cystic fibrosis and functional assessment of the chloride channel with the pathogenic variant c.831G>A (p.Trp277*), described for the first time

Cited by 7 publications

References 14 publications

Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy

Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy

Personalized Selection of a CFTR Modulator for a Patient with a Complex Allele [L467F;F508del]

Frequency Analysis Results Distribution of C589t Rs2243250 Polymorphism in Il4 Gene Among Patients with Chronic Rhinosinusitis

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