Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis
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Published:2023-03-28
Issue:7
Volume:24
Page:6351
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Kondratyeva Elena1ORCID, Melyanovskaya Yuliya1ORCID, Bulatenko Nataliya1, Davydenko Ksenia1ORCID, Filatova Alexandra1, Efremova Anna1, Skoblov Mikhail1ORCID, Bukharova Tatiana1ORCID, Sherman Viktoriya1ORCID, Voronkova Anna1ORCID, Zhekaite Elena1, Krasovskiy Stanislav12, Amelina Elena12, Petrova Nika1, Polyakov Alexander1, Adyan Tagui1, Starinova Marina1, Krasnova Maria1, Vasilyev Andrey1ORCID, Makhnach Oleg1ORCID, Zinchenko Rena1ORCID, Kutsev Sergey1, Gokdemir Yasemin3, Karadag Bülent3ORCID, Goldshtein Dmitry1
Affiliation:
1. Research Centre for Medical Genetics, 1 Moskvorechye St., 115552 Moscow, Russia 2. Pulmonology Scientific Research Institute, Federal Medical and Biological Agency of Russian Federation, Orekchovy Boulevard, 28, 115682 Moscow, Russia 3. Division of Pediatric Pulmonology, Marmara University, 34722 Istanbul, Turkey
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 RT-PCR products obtained from patients’ intestinal organoid cultures were analyzed. Patients with the genetic variant E92K are characterized by an older age of diagnosis compared to homozygotes F508del and a high frequency of pancreatic sufficiency. The results of the sweat test and the ICM method showed partial preservation of the function of the CFTR channel. Functional analysis of CFTR gene expression revealed a weak effect of the E92K variant on mRNA-CFTR splicing. Lumacaftor (VX-809) has been shown to restore CFTR function in an intestinal organoid model, which allows us to consider the E92K variant as a promising target for therapy with CFTR correctors.
Funder
Federal State Funded Research Institution “Research Centre for Medical Genetics”
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference46 articles.
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