The presence of pathogenic variants in the CFTR gene causes cystic fibrosis (CF) through various molecular mechanisms that affect the formation and functional activity of the CFTR chloride channel. An important factor affecting the phenotypic manifestations of CF and the effectiveness of targeted therapy is the presence of complex alleles with > 2 consecutive mutations per 1 allele, or in the cis position. The influence of complex alleles on the manifestations of CF has not been sufficiently studied globally due to the small number of studies.The aim of the study was to investigate the influence of the complex allele [S466X; R1070Q] on the phenotypic manifestations of CF and the effectiveness of targeted therapy in a model of intestinal organoids from a patient with [S466X; R1070Q]/CFTRdele2,3 genotype.Methods. We used medical history data, intestinal current measurement, intestinal organoid method, and forskolin test.Results. The progressive nature of the disease with a clear degradation of lung function was established. The ICM method showed absent chloride channel function. The tests on the culture of organoids obtained from the intestinal tissue indicated a complete loss of the chloride channel function. In addition, the complex allele [S466X; R1070Q] was insensitive to all targeted drugs tested.Conclusion. The complex allele [S466X; R1070Q] causes a complete loss of the functional CFTR protein and is not sensitive to any of the approved targeted drugs.
Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease, associated with pathogenic variants in the CFTR gene. The splicing variant c.3140-16T>A (3272-16T>A) has been described previously and, according to the Russian CF Patients Registry, occurs with a frequency of 0.34%. The phenotypic features of CF patients with the c.3140-16T>A variant were compared with those of patients with the genotype F508del/F508del. Patients with the allele c.3140-16T>A had higher average age and age at diagnosis, and the allele was present in a greater proportion of adults. Patients carrying the c.3140-16T>A allele were characterised by better physical development indicators, both in adults and in children, had preserved pancreatic function, as well as the absence of a number of complications, and required pancreatic enzyme replacement therapy less often than patients with the F508del/F508del genotype. Sweat test values also were lower in patients with the c.3140-16T>A genotype. According to the results of clinical and laboratory studies, the phenotype of patients with the genetic variant c.3140-16T>A can be considered “mild”. Functional CFTR protein activity in the presence of c.3140-16T>A was evaluated using intestinal current measurements (ICM) and the forskolin-induced swelling assay on organoids obtained from patients’ rectal biopsies. c.3140-16T>A had high residual CFTR channel activity and was amenable to effective pharmacological correction with thea VX-770 potentiator. To evaluate the effect of the variant on CFTR pre-mRNA splicing we performed a minigene assay, as well as RT-PCR analysis of RNA isolated from the nasal epithelium and rectal biopsy of patients. We showed that the c.3140-16T>A variant creates a novel acceptor AG dinucleotide within CFTR intron 19, resulting in a 14-nucleotide extension of exon 20. This frameshift produces a premature termination codon and triggers mRNA degradation by the nonsense-mediated decay (NMD) mechanism. Moreover, we observed that the c.3140-16T>A allele could produce a residual amount of normally spliced transcript, thus explaining the patient’s mild phenotype.
Научно-исследовательский институт пульмонологии, москва, Российская Федерация 2 медико-генетический научный центр им. академика Н. п. Бочкова, москва, Российская Федерация 3 Российский национальный исследовательский медицинский университет им. Н. И. пирогова, москва, Российская Федерация genophenoTYpic relaTionships in cYsTic fiBrosis on The Basis of 2017 naTional regisTer DaTa Krasovsky s. a. 1, 2 , Kondratyeva e. i. 2 , chernyak a. V. 1 , Kashirskaya n. Yu. 2 , adyan T. a. 2 , amelina e. l. 1 , Voronkova a. Yu. 2 , Zonenko o. g. 3 1 scientific research institute of pulmonology, moscow, russian federation 2 research center for medical genetics, moscow, russian federation 3 russian national research medical university named after n. i. pirogov, moscow, russian federation мЕДИЦИНСКИЙ ВЕСТНИК СЕВЕРНОГО КАВКАЗА 2020. Т. 15. № 2 meDical neWs of norTh caucasus 2020. Vоl. 15. iss. 2
The major risk factor for death in cystic fibrosis (CF) is a progressive lung injury; however, low nutritional status (NS) remains an important and underestimated problem in the management of these patients. The NS of a patient with CF is impaired by many factors, such as chronic malabsorption, pancreatic failure, chronic inflammation, and recurrent pulmonary infection - they all lead to higher energy demand in the presence of lower intake of nutrients. The NS of those with CF plays an important role in maintaining lung function. The patients with higher NS have longer life expectancies. According to the Russian National Registry, both pediatric and adult patients with CF have shorter life expectancies. The article discusses various nutritional support regimens and their impact on lung function parameters.
1 пермский государственный медицинский университет им. Е. А. Вагнера, Российская Федерация 2 Научно-исследовательский институт пульмонологии, москва, Российская Федерация 3 медико-генетический научный центр им. академика Н. п. Бочкова, москва, Российская Федерация epiDemiological anD clinical feaTures of «miDDle-urals» VarianT L138ins in cYsTic fiBrosis shadrina V. V. 1 , Krasovsky s. a. 2 , Kondratyeva e. i. 3 , furman e. g. 1 1 e. a. Vagner perm state medical university, russian federation 2 scientific research institute of pulmonology, moscow, russian federation 3 research centre for medical genetics, moscow, russian federation Представлен обзор литературы, посвященный патогенному варианту L138ins в гене CFTR при муковисцидозе. Вариант L138ins редко встречается в мире, однако часто регистрируется на Среднем Урале. До внедрения неонатального скрининга у пациентов с L138ins отмечалась поздняя диагностика заболевания. Клинически L138ins связан с формированием «мягкого» фенотипа муковисцидоза. При применении препаратов, влияющих на работу CFTR, положительный ответ получен на корректор CFTR люмакафтор и комбинацию люмакафтор/ивакафтор, что обусловлено расположением L138ins в гене CFTR.
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