scholarly journals Clinical and genetic features of cystic fibrosis patients with novel pathogenic variant CFTR c.1083G> A (p.Trp361*) and functional assessment of the activity of the chloride channel

2019 ◽  
pp. 9-18
Author(s):  
Е.И. Кондратьева ◽  
Ю.Л. Мельяновская ◽  
А.С. Ефремова ◽  
Н.В. Булатенко ◽  
Т.Б. Бухарова ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Russian Federation ◽  
Genetic Variant ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Intestinal Organoids ◽  
The Russian Federation ◽  
First Time

В статье впервые представляется клинико-генетическая характеристика мутации c.1083G>A (p.Trp361*) в гене CFTR. Патогенный генетический вариант c.1083G>A (p.Trp361*) гена CFTR относится к нонсенс-мутациям (I класс) и впервые был внесён в базу данных CFTR1 (http://www.genet.sickkids.on.ca) в середине 2019 г. без описания клинической картины муковисцидоза. Методы. Проведен анализ амбулаторных карт и историй болезни двух пациентов из неродственных семей с редким генетическим вариантом c.1083G>A (p.Trp361*). Для определения разности кишечных потенциалов (ОРКП) и проведения форсколинового теста на кишечных органоидах использовали биопсийный материал слизистой прямой кишки пациентов. ДНК для секвенирования выделяли из лейкоцитов венозной крови пациентов. Результаты. Анализ клинических проявлений заболевания у детей 6 и 9 лет показал наличие хронической панкреатической недостаточности, более выраженной у одного ребенка с синдромом дистальной интестинальной обструкции кишечника в анамнезе. Клиническая картина второго пациента характеризовалась развитием в раннем возрасте транзиторной гипербилирубинемии, синдрома псевдо-Барттера, а в дальнейшем - повторными эпизодами бронхиальной обструкции и развитием полипозного риносинусита. ОРКП и форсколиновый тест на кишечных органоидах показали, что генетический вариант c.1083G>A (p.Trp361*) относится к вариантам гена CFTR с отсутствием функции хлорного канала. Выводы. Впервые представлены описание клинической картины муковисцидоза у двух пациентов из неродственных семей с патогенным вариантом c.1083G>A (p.Trp361*) в компаунде с вариантом c.1521_1523delCTT (p.Phe508del) (ранее называемом F508del) и результаты оценки функции белка CFTR методом ОРКП и форсколиновым тестом на кишечных органоидах. In this article we continue to describe the pathogenic variants of the CFTR gene identified among Russian cystic fibrosis (CF) patients. For the first time the clinical and genetic characteristics of the mutation c.1083G> A (p.Trp361 *) are presented. The pathogenic genetic variant c.1083G> A (p.Trp361 *) of the CFTR gene belongs to the nonsense mutations (class I) and was listed for the first time in the CFTR1 database (http://www.genet.sickkids.on.ca) by Professor Milan Macek et al. in mid-2019 without any description of clinical manifestations of cystic fibrosis. Methods. The data of the National Register of Patients with Cystic Fibrosis of the Russian Federation 2017 were analyzed. Outpatient records and case histories of two patients from unrelated families carrying a rare genetic variant c.1083G> A (p.Trp361 *) were analyzed. To determine the Intestinal current measurement (ICM) and Forskolin-induced swelling (FIS) in intestinal organoids, rectal biopsy material of CF patients was used. DNA for sequencing was isolated from leukocytes of venous blood of the patients. Results. Variant c.1083G> A (p.Trp361 *) was found in two patients from unrelated families from different regions of the Russian Federation, according to the Register of Cystic Fibrosis Patients in the Russian Federation 2017. Analysis of clinical manifestations of the disease in children 6 and 9 years old showed the presence of chronic pancreatic insufficiency, more expressed in one child with a history of distal intestinal obstruction syndrome. The clinical manifestation of the second patient was characterized by the development of transient hyperbilirubinemia, Pseudo-Bartter’s syndrome at an early age, and subsequently repeated episodes of bronchial obstruction and the development of polypoid rhinosinusitis. The ICM method and the FIS in intestinal organoids showed that the genetic variant c.1083G> A (p.Trp361 *) refers to the variants of the CFTR gene with the absence of chlorine channel function. Conclusion. The clinical picture of cystic fibrosis in two patients from unrelated families with the pathogenic variant c.1083G> A (p.Trp361 *) in the compound with variant c.1521_1523delCTT (p.Phe508del) (variant legacy name F508del) and results of the evaluation of the CFTR protein functions, obtained by the method of ICM and using the FIS assay in intestinal organoids, are presented for the first time. Patients continue to be under the control in Russian CF centers.

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.

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 ORGANIZATION OF AID IN CYSTIC FIBROSIS PATIENTS IN THE NORTH-CAUCASIAN FEDERAL REGION

2019 ◽  
Vol 20 (2) ◽  
pp. 84-89
Author(s):  
E. V. Vodovozova ◽  
L. N. Ledeneva ◽  
N. I. Kapranov ◽  
T. A. Ponomareva ◽  
I. V. Polyakova ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Short Duration ◽  
Russian Federation ◽  
Social Problem ◽  
Clinical Manifestations ◽  
Hereditary Disease ◽  
The North ◽  
Regional Center ◽  
Therapeutic Measures ◽  
The Russian Federation

Cistic fibrosis (CF) is the hereditary disease, presenting the important medical social problem, related with timely diagnostics, the early disablement of patients, short duration of their life, need for a constant performing therapeutic measures and active clinic observation. In 2008 in the North-Caucasian Federal Region (NCFR), there was introduced the register of СF patients, in 2015 the data about patients residing in the Stavropol territory were sent for the introduction into the register of CF cases of the Russian Federation. The executed analysis showed the register of СF cases of the Russian Federation to be is insufficiently used in all NCFR regions, which makes impossible the processing of data about the special features of the course, the clinical manifestations, epidemiology, genetic inspection, microbiological monitoring and treatment of the disease in the region. The implemented analysis of the management of СF patients in NCFR, determines the need of creating the united regional center for the improvement of the centralized aid for considered patients.

Description of rare alleles of the CFTR gene in cystic fibrosis using functional tests and forskolin-induced swelling assay in rectal organoids

2021 ◽  
Vol 31 (2) ◽  
pp. 178-188
Author(s):  
A. S. Efremova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Bulatenko ◽  
N. D. Odinaeva ◽  
A. V. Orlov ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Venous Blood ◽  
Clinical Manifestations ◽  
Rectal Biopsy ◽  
Hereditary Disease ◽  
Cftr Gene ◽  
Functional Assay ◽  
Functional Protein ◽  
Blood Leukocytes ◽  
Intestinal Organoids

Cystic fibrosis (CF) is a systemic hereditary disease caused by a mutation of the CFTR gene and characterized by damage to the glands of external secretion and severe dysfunctions of the respiratory system. The “severe” genotypes are associated with more pronounced and early clinical manifestations. The “mild” genotypes are associated with a delayed onset of clinical manifestations.Methods. An analysis of the medical history of patients with asymptomatic CF from the Russian CF centers was carried out. Rectal biopsy specimens were used for intestinal current measurement (ICM) and forskolin-induced swelling assay in intestinal organoids. DNA for sequencing was isolated from the venous blood leukocytes.Results. 2 CF patients with genotypes F508del/c.1584+18672A>G (patient 1, 12 years old) and F508del/G509D-E217G (patient 2, 3 years old) were examined. The diagnosis was based on neonatal screening. The ICM assay showed a reduced function of the CFTR channel: ΔISC for forskolin was 12.33 ± 2.35 μA/cm2 in patient 1 and 25 ± 3.37 μA/cm2 in patient 2. The negative response to carbachol and histamine reflects the entry of potassium ions into the cells, which is typical for CF. The assay in intestinal organoids showed that the amount of functional protein on the apical membrane of the intestinal epithelium increases both under the action of the potentiator and the corrector in both patients. The greatest effect is observed when the VX-770 and VX-809 are used together.Conclusion. The ICM functional assay and the forskolin-induced swelling assay in intestinal organoids are sensitive enough to determine the residual functional activity of the CFTR channel and clarify the diagnosis in difficult cases. The studied genetic variants c.1584+18672A>G and G509D-E217G belong to class IV – VI mutations. The clinical picture corresponds to the manifestations of “mild” mutations. The studied patients still attend the Russian cystic fibrosis centers.

WS02.3 Liver cirrhosis and transplantation in cystic fibrosis in the Russian Federation

2021 ◽  
Vol 20 ◽  
pp. S4
Author(s):  
E. Zhekaite ◽  
E. Kondratyeva ◽  
A. Voronkova ◽  
V. Sherman ◽  
T. Dzhanbekov ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Liver Cirrhosis ◽  
Russian Federation ◽  
The Russian Federation

Molecular Epidemiological Monitoring of Circulation of Coxsackievirus A10

2021 ◽  
pp. 43-49
Author(s):  
LN Golitsyna ◽  
VV Zverev ◽  
NV Ponomareva ◽  
NI Romanenkova ◽  
Thao Thanh Thi Nguyen ◽  
...  
Keyword(s):  
Russian Federation ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Foot And Mouth Disease ◽  
Sewage Water ◽  
Epidemiological Surveillance ◽  
Molecular Monitoring ◽  
South Vietnam ◽  
Epidemiological Monitoring ◽  
The Russian Federation

Background: Coxsackievirus A10 (CV-A10) is currently one of the most common etiological agents of enterovirus infection (EVI). Over the past decade, severe and fatal cases of CV-A10 infection have become more frequent while clinical manifestations of the disease are similar to those of Enterovirus A71 infection. The objective of our study was to characterize circulation of Coxsackievirus A10 in the Russian Federation in 2008–2019 and to study the phylogenetic relationships of strains isolated in Russia and Vietnam. Materials and methods: In 2008–2019, 220 CV-A10 strains were isolated from patients with various clinical manifestations of EVI and from sewage water samples taken in the Russian Federation and then studied using molecular genetic methods. In addition to that, we analyzed 26 CV-A10 strains isolated from patients with hand, foot, and mouth disease (HFMD) and acute flaccid paralysis in South Vietnam in 2018–2019. Results: We established a two-year periodicity of CV-A10 active circulation in Russia. In the structure of clinical forms of CV-A10 infection, herpetic angina prevailed (30.8 %), followed by minor illness (25.25 %), respiratory diseases (15.66 %), exanthema (14.65 %), gastrointestinal disorders (8.08 %), and asymptomatic infections (2.02 %). Symptoms of CNS damage (meningitis, meningoencephalitis) were observed in 3.53 % of cases. Most CV-A10 strains from Vietnam were isolated from patients with CNS affection of varying degrees of severity. During the study period, CV-A10 strains of genotypes C, E, and F3 circulated in the territory of the Russian Federation whereas the strains from South Vietnam were represented by genotypes F3 and F1. The studied strains showed a genetic relationship with those of CV-A10 circulating in different countries. Vietnamese and some Russian strains of the F3 genotype were genetically close to the strains isolated from severe cases. Conclusions: Molecular monitoring of CV-A10 circulation is an important component of the global epidemiological surveillance of EVI.

scholarly journals About the Results of Monitoring Researches of Ballast Waters and Data of Identification of the Vibrioes Strains Selected During the Ships Researches in Russian Seaports in 2018

2020 ◽  
Vol 97 (1) ◽  
pp. 55-61
Author(s):  
S. Yu. Vodyanitskаyа ◽  
O. V. Sergienko ◽  
N. G. Ivanova ◽  
V. V. Balachnova ◽  
I. V. Arkhangelskаya ◽  
...  
Keyword(s):  
Russian Federation ◽  
Ballast Water ◽  
International Convention ◽  
International Standard ◽  
E Coli ◽  
Ballast Waters ◽  
Rostov Region ◽  
Intestinal Infections ◽  
The Russian Federation ◽  
First Time

Relevance. In September, 2017 the International Convention on Control of Ships’ Ballast Waters and sediments, in which the Russian Federation takes part, came into effect.Aim of article is to cover the results of implementation of the Convention in Russia, regarding selection and analysis of ballast waters tests for compliance with the international standard.Material and methods. The materials for work were data on ship arrivals at the international seaports of the Russian Federation, provided by sanitary and quarantine departments of the Russian ports, and monitoring researches of ballast waters in seaports of some regions of the Russian Federation. Analytical, bacteriological, molecular methods were applied.Results. The studies of ballast waters in the Leningrad and Kaliningrad regions have been conducted for the first time in 2018, and in the Rostov region the study lasts since 2010. The laboratory researches of ships’ ballast showed that E. coli, Enterococcus spp. were in norm, V. cholerae O1 and O139 in ballast were absent. 12 of 21 ballast water tests investigated by specialists of the Rostov region laboratories contained V. cholerae non-O1/non-O139, ballast was taken on the ships which arrived from Romania and Turkey.Сonclusion. The results of the molecular and genetic researches suggest that there is a probability of V. сholeraе introduction brougth with ship ballast. Management decisions are demanded to ensure biological safety of shipping and to decrease intestinal infections incidence in residents of the seaside cities.

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