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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Apr 13

PMID 37047318

Authors

Elena Kondratyeva

Yuliya Melyanovskaya

Nataliya Bulatenko

Ksenia Davydenko

Alexandra Filatova

Anna Efremova

Mikhail Skoblov

Tatiana Bukharova

Viktoriya Sherman

Anna Voronkova

Elena Zhekaite

Stanislav Krasovskiy

Elena Amelina

Nika Petrova

Alexander Polyakov

Tagui Adyan

Marina Starinova

Maria Krasnova

Andrey Vasilyev

Oleg Makhnach

Rena Zinchenko

Sergey Kutsev

Yasemin Gokdemir

Bulent Karadag

Dmitry Goldshtein

Affiliations

Soon will be listed here.

Abstract

The pathogenic variant E92K (c.274G > A) of the 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 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.

Citing Articles

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

Kondratyeva E, Melyanovskaya Y, Sherman V, Voronkova A, Zhekaite E, Krasovsky S Front Genet. 2024; 15:1383033.

PMID: 39529847 PMC: 11551019. DOI: 10.3389/fgene.2024.1383033.

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

Kondratyeva E, Melyanovskaya Y, Efremova A, Krasnova M, Mokrousova D, Bulatenko N Genes (Basel). 2023; 14(9).

PMID: 37761847 PMC: 10530926. DOI: 10.3390/genes14091705.

References

Vonk A, van Mourik P, Ramalho A, Silva I, Statia M, Kruisselbrink E . Protocol for Application, Standardization and Validation of the Forskolin-Induced Swelling Assay in Cystic Fibrosis Human Colon Organoids. STAR Protoc. 2020; 1(1):100019. PMC: 7580120. DOI: 10.1016/j.xpro.2020.100019. View

Joynt A, Evans T, Pellicore M, Davis-Marcisak E, Aksit M, Eastman A . Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies. PLoS Genet. 2020; 16(10):e1009100. PMC: 7605713. DOI: 10.1371/journal.pgen.1009100. View

Van Goor F, Yu H, Burton B, Hoffman B . Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2013; 13(1):29-36. DOI: 10.1016/j.jcf.2013.06.008. View

Stanke F, Ballmann M, Bronsveld I, Dork T, Gallati S, Laabs U . Diversity of the basic defect of homozygous CFTR mutation genotypes in humans. J Med Genet. 2008; 45(1):47-54. DOI: 10.1136/jmg.2007.053561. View

Bienvenu T, Lopez M, Girodon E . Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges. Genes (Basel). 2020; 11(6). PMC: 7349214. DOI: 10.3390/genes11060619. View

Berger H, Travis S, Welsh M . Regulation of the cystic fibrosis transmembrane conductance regulator Cl- channel by specific protein kinases and protein phosphatases. J Biol Chem. 1993; 268(3):2037-47. View

Awatade N, Ramalho S, Silva I, Felicio V, Botelho H, de Poel E . R560S: A class II CFTR mutation that is not rescued by current modulators. J Cyst Fibros. 2018; 18(2):182-189. DOI: 10.1016/j.jcf.2018.07.001. View

Castellani C, Duff A, Bell S, Heijerman H, Munck A, Ratjen F . ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018; 17(2):153-178. DOI: 10.1016/j.jcf.2018.02.006. View

Ren H, Grove D, De La Rosa O, Houck S, Sopha P, Van Goor F . VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell. 2013; 24(19):3016-24. PMC: 3784376. DOI: 10.1091/mbc.E13-05-0240. View

10.

Boj S, Vonk A, Statia M, Su J, Vries R, Beekman J . Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients. J Vis Exp. 2017; (120). PMC: 5408767. DOI: 10.3791/55159. View

11.

Bell S, De Boeck K, Amaral M . New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther. 2014; 145:19-34. DOI: 10.1016/j.pharmthera.2014.06.005. View

12.

Castellani C, Cuppens H, Macek Jr M, Cassiman J, Kerem E, Durie P . Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008; 7(3):179-96. PMC: 2810954. DOI: 10.1016/j.jcf.2008.03.009. View

13.

Beekman J . Individualized medicine using intestinal responses to CFTR potentiators and correctors. Pediatr Pulmonol. 2016; 51(S44):S23-S34. DOI: 10.1002/ppul.23553. View

14.

Ramalho A, Furstova E, Vonk A, Ferrante M, Verfaillie C, Dupont L . Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis. Eur Respir J. 2020; 57(1). DOI: 10.1183/13993003.02426-2019. View

15.

Graeber S, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S . Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2018; 197(11):1433-1442. DOI: 10.1164/rccm.201710-1983OC. View

16.

Derichs N, Sanz J, von Kanel T, Stolpe C, Zapf A, Tummler B . Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data. Thorax. 2010; 65(7):594-9. DOI: 10.1136/thx.2009.125088. View

17.

Nunes V, Chillon M, Dork T, Tummler B, Casals T, Estivill X . A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype. Hum Mol Genet. 1993; 2(1):79-80. DOI: 10.1093/hmg/2.1.79. View

18.

Stepanova A, Abrukova A, Savaskina E, Poliakov A . [Mutation p.E92K is the primary cause of cystic fibrosis in Chuvashes]. Genetika. 2012; 48(7):863-71. View

19.

Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman H . Nutrition in patients with cystic fibrosis: a European Consensus. J Cyst Fibros. 2004; 1(2):51-75. DOI: 10.1016/s1569-1993(02)00032-2. View

20.

Dekkers J, van der Ent C, Beekman J . Novel opportunities for CFTR-targeting drug development using organoids. Rare Dis. 2014; 1:e27112. PMC: 3915567. DOI: 10.4161/rdis.27112. View