Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis

Kondratyeva, E.I.; Melyanovskaya, Y.; Bulatenko, N.; Davydenko, Ksenia; Filatova, Alexandra; Ефремова, А.; Skoblov, Mikhail; Бухарова, Т. Б.; Sherman, V.D.; Voronkova, A.; Zhekaite, E.; Krasovskiy, S.; Amelina, E.; Petrova, N.V.; Polyakov, A. V.; Adyan, T.; Starinova, M.; Krasnova, Maria; Vasilyev, A. V.; Makhnach, O. V.; Зинченко, Р. А.; Kutsev, Sergey I.; Gökdemir, Yasemin; Karadağ, Bülent; Goldshtein, D. V.

doi:10.3390/ijms24076351

IJMS

2023

DOI: 10.3390/ijms24076351

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Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis

E.I. Kondratyeva

Y. Melyanovskaya

N. Bulatenko

et al.

Abstract: The pathogenic variant E92K (c.274G > A) of the CFTR gene is rare in America and Europe, but it is common for people with cystic fibrosis from Russia and Turkey. We studied the effect of the E92K genetic variant on the CFTR function. The function of the CFTR channel was studied using the intestinal current measurements (ICM) method. The effects of CFTR modulators on the restoration of the CFTR function were studied in the model of intestinal organoids. To assess the effect of E92K on pre-mRNA splicing, the … Show more

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Cited by 3 publications

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Personalized assessment of the effectiveness of targeted drugs for the treatment of cystic fibrosis in a patient with c.264_268delATATT and c.3139+1G>C rare variants of the <i>CFTR</i> gene

Efremova,

Sherman,

Melyanovskaya

et al. 2024

Genes & Cells

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When new, most often rare variants of the CFTR gene are detected in patients with cystic fibrosis, the method of intestinal organoids is used, which allows for a personalized assessment of the residual functional activity of the CFTR channel and the effect of targeted drugs to determine the possibility of further pathogenetic therapy. Objective: to study the effect of the CFTR potentiator ivacaftor, as well as ivacaftor in combination with the CFTR correctors lumacaftor, tezacaftor and elexacaftor on the restoration of CFTR-channel function on a culture of intestinal organoids obtained from a patient with two rare variants c.264_268delATATT and c.3139+1GC. To assess the activity of the CFTR channel, the forskolin-induced swelling assay on organoids and the intestinal current measurements on rectal biopsy samples method were used, a description of the clinical picture in a patient with the c.264_268delATATT/c.3139+1GC genotype was performed. Genetic variants c.264_268delATATT and c. 3139+1GC are classified as "severe" and cause complete loss of CFTR chloride channel function. The severity of the disease in a child is consistent with in vitro results. No effective CFTR modulators were found for the studied variants, so targeted therapy cannot be recommended to the patient.

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Personalized assessment of the effectiveness of targeted drugs for the treatment of cystic fibrosis in a patient with c.264_268delATATT and c.3139+1G>C rare variants of the <i>CFTR</i> gene

Efremova,

Sherman,

Melyanovskaya

et al. 2024

Genes & Cells

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show abstract

Study of the genetic and molecular epidemiology of cystic fibrosis based on the patient registry for planning targeted therapy in Russian Federation

Kondratyeva,

Melyanovskaya,

Sherman

et al. 2024

Front. Genet.

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Cystic fibrosis (CF) is a genetically inherited disorder characterized by a wide range of clinical manifestations and genetic variations. This study focuses on the genetic and molecular epidemiology of CF in the Russian population, utilizing data from the national CF registry. The birth prevalence of CF in Russia has been analyzed over a span of years, revealing variations in frequency. The study delves into the genetic landscape of CFTR gene variants in Russian patients, showcasing a diverse spectrum with a predominance of severe variants, some of which are rare and distinct from global populations. A total of 233 variants have been documented, exhibiting frequencies ranging from 0.01% to 51.5%, with 47 of these variants remaining uncharted within international genetic databases. As of 2021, CFTR modulator therapy has been introduced for patients under 19 years, heightening the importance of genetic diagnosis. In 2023, more than 1,850 patients under 19 received CFTR modulator therapy. Notably, the impact of complex alleles on disease progression and response to targeted therapies is gaining recognition. Comparisons with European registries highlight distinctive features of the Russian population, such as differences in age distribution among patients. Additionally, the study emphasizes the need to ascertain clinical significance and pathogenicity of newly identified genetic variants, along with exploring their suitability for targeted therapies. The integration of genetic insights into the management of CF offers potential for enhanced personalized therapeutic interventions. In conclusion, this thorough analysis provides a comprehensive understanding of the genetic nuances within the Russian CF population. By illuminating the intricate relationship between genetic variations and disease manifestation, the study underscores the essential role of genetics in shaping therapeutic strategies and improving patient outcomes. Further research and ongoing genetic exploration are crucial for optimizing the care of individuals with CF in the era of evolving therapeutic options.

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Clinical and Genetic Characteristics of a Patient with Cystic Fibrosis with a Complex Allele [E217G;G509D] and Functional Evaluation of the CFTR Channel

Kondratyeva,

Melyanovskaya,

Efremova

et al. 2023

Genes

Self Cite

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The intricate nature of complex alleles presents challenges in the classification of CFTR gene mutations, encompassing potential disease-causing, neutral, or treatment-modulating effects. Notably, the complex allele [E217G;G509D] remains absent from international databases, with its pathogenicity yet to be established. Assessing the functionality of apical membrane ion channels in intestinal epithelium employed the intestinal current measurements (ICM) method, using rectal biopsy material. The effectivity of CFTR-targeted therapy was evaluated using a model of intestinal organoids of a patient harboring the genotype F508del/[E217G;G509D]. ICM analysis revealed diminished chloride channel function. Remarkably, [E217G;G509D] presence within intestinal organoids correlated with heightened residual CFTR function. Employing CFTR modulators facilitated the restoration of the functional CFTR protein. This multifaceted study intertwines genetic investigations, functional analyses, and therapeutic interventions, shedding light on the intricate interplay of complex alleles within CFTR mutations. The results highlight the potential of targeted CFTR modulators to restore functional integrity, offering promise for advancing precision treatments in cystic fibrosis management.

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Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis

Cited by 3 publications

References 35 publications

Personalized assessment of the effectiveness of targeted drugs for the treatment of cystic fibrosis in a patient with c.264_268delATATT and c.3139+1G>C rare variants of the <i>CFTR</i> gene

Personalized assessment of the effectiveness of targeted drugs for the treatment of cystic fibrosis in a patient with c.264_268delATATT and c.3139+1G>C rare variants of the <i>CFTR</i> gene

Study of the genetic and molecular epidemiology of cystic fibrosis based on the patient registry for planning targeted therapy in Russian Federation

Clinical and Genetic Characteristics of a Patient with Cystic Fibrosis with a Complex Allele [E217G;G509D] and Functional Evaluation of the CFTR Channel

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