{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:22:56Z","timestamp":1791508976738,"version":"4.3.4"},"reference-count":23,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Science Foundation","award":["22-15-00473"],"award-info":[{"award-number":["22-15-00473"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the Russian population of patients with CF is 0.74%, and in patients with the F508del\/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele [L467F;F508del] in a cohort of patients with genotypes [L467F;F508del]\/class I (c.3532_3535dup, c.1766+2T&gt;C, W1310X, 712-1G&gt;T), and data for a unique patient with the genotype [L467F;F508del]\/[L467F;F508del]. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for [L467F;F508del]\/class I and [L467F;F508del]\/[L467F;F508del] genotypes. In intestinal organoids, it was shown that [L467F;F508del] in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6\u201312 months.<\/jats:p>","DOI":"10.3390\/ijms251910424","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T06:10:27Z","timestamp":1727417427000},"page":"10424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Estimation of Chloride Channel Residual Function and Assessment of Targeted Drugs Efficiency in the Presence of a Complex Allele [L467F;F508del] in the CFTR Gene"],"prefix":"10.3390","volume":"25","author":[{"given":"Anna","family":"Efremova","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8814-5532","authenticated-orcid":false,"given":"Yuliya","family":"Melyanovskaya","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Krasnova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Voronkova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Mokrousova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zhekaite","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Bulatenko","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Makhnach","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0481-256X","authenticated-orcid":false,"given":"Tatiana","family":"Bukharova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei","family":"Kutsev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Goldshtein","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6395-0407","authenticated-orcid":false,"given":"Elena","family":"Kondratyeva","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/j.jcf.2019.12.008","article-title":"The influence of CFTR complex alleles on precision therapy of cystic fibrosis","volume":"19","author":"Chevalier","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.jcf.2018.12.011","article-title":"Predictive factors for lumacaftor\/ivacaftor clinical response","volume":"18","author":"Masson","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/jhg.2016.15","article-title":"The novel complex allele [A238V;F508del] of the CFTR gene: Clinical phenotype and possible implications for cystic fibrosis etiological therapies","volume":"61","author":"Diana","year":"2016","journal-title":"J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1136\/jmedgenet-2016-103985","article-title":"Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles","volume":"54","author":"Terlizzi","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kleinfelder, K., Somenza, E., Farinazzo, A., Conti, J., Lotti, V., Latorre, R.V., Rodella, L., Massella, A., Tomba, F., and Bertini, M. (2023). CFTR Modulators Rescue the Activity of CFTR in Colonoids Expressing the Complex Allele p.[R74W;V201M;D1270N]\/dele22_24. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065199"},{"key":"ref_6","first-page":"145","article-title":"Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone","volume":"105","author":"Romey","year":"1999","journal-title":"Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/humu.22129","article-title":"CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes","volume":"33","author":"Girodon","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_8","unstructured":"Krasovsky, S.A., Starinova, M.A., Voronkova, A.Y., Amelina, E.L., Kashirskaya, N.Y., Kondratyeva, E.I., and Nazarenko, L.P. (2023). Register of Patients with Cystic Fibrosis in the Russian Federation, Publishing House Foundation \u00abOstrova\u00bb. 2021 Year."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/humu.23389","article-title":"Cis Variants Identified in F508del Complex Alleles Modulate CFTR Channel Rescue by Small Molecules","volume":"39","author":"Baatallah","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kondratyeva, E., Efremova, A., Melyanovskaya, Y., Voronkova, A., Polyakov, A., Bulatenko, N., Adyan, T., Sherman, V., Kovalskaia, V., and Petrova, N. (2022). Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810377"},{"key":"ref_11","first-page":"162","article-title":"Determination of reference values for the method of intestinal current measurement in the Russian Federation","volume":"15","author":"Melyanovskaya","year":"2020","journal-title":"Med. News North Cauc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"344ra84","DOI":"10.1126\/scitranslmed.aad8278","article-title":"Characterizing Responses to CFTR-Modulating Drugs Using Rectal Organoids Derived from Subjects with Cystic Fibrosis","volume":"8","author":"Dekkers","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2353\/jmoldx.2006.050063","article-title":"A haplotype framework for cystic fibrosis mutations in Iran","volume":"8","author":"Elahi","year":"2006","journal-title":"J. Mol. Diagn."},{"key":"ref_14","first-page":"16038","article-title":"Deep resequencing of CFTR in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits","volume":"24","author":"Blackman","year":"2016","journal-title":"Hum. Genome Var."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sondo, E., Cresta, F., Pastorino, C., Tomati, V., Capurro, V., Pesce, E., Lena, M., Iacomino, M., Baffico, A.M., and Coviello, D. (2022). The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor\/Tezacaftor\/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063175"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Terlizzi, V., Centrone, C., Ferrari, B., Castellani, C., Gunawardena, T.N.A., Taccetti, G., and Laselva, O. (2022). Modulator Therapy in Cystic Fibrosis Patients with Cis Variants in F508del Complex Allele: A Short-Term Observational Case Series. J. Pers. Med., 12.","DOI":"10.3390\/jpm12091421"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"264","DOI":"10.18093\/0869-0189-2024-34-2-264-270","article-title":"Functional activity of the CFTR channel in a patient with the [L467F;F508del]\/W1310X genotype","volume":"34","author":"Krasnova","year":"2024","journal-title":"Pulmonologiya"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.18093\/0869-0189-2023-33-2-233-242","article-title":"Description of the clinical picture and assessment of the functional activity of the CFTR channel in a patient with a complex allele [S466X;R1070Q]","volume":"33","author":"Krasnova","year":"2023","journal-title":"Pulmonologiya"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1136\/thx.2009.125088","article-title":"Intestinal Current Measurement for Diagnostic Classification of Patients with Questionable Cystic Fibrosis: Validation and Reference Data","volume":"65","author":"Derichs","year":"2010","journal-title":"Thorax"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1002\/ppul.23773","article-title":"Toward inclusive therapy with CFTR modulators: Progress and challenges","volume":"52","author":"Guimbellot","year":"2017","journal-title":"Pediatr. Pulmonol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Clancy, J.P., Szczesniak, R.D., Ashlock, M.A., Ernst, S.E., Fan, L., Hornick, D.B., Karp, P.H., Khan, U., Lymp, J., and Ostmann, A.J. (2013). Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073905"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100019","DOI":"10.1016\/j.xpro.2020.100019","article-title":"Protocol for Application, Standardization and Validation of the Forskolin-Induced Swelling Assay in Cystic Fibrosis Human Colon Organoids","volume":"1","author":"Vonk","year":"2020","journal-title":"STAR Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1902426","DOI":"10.1183\/13993003.02426-2019","article-title":"Correction of CFTR Function in Intestinal Organoids to Guide Treatment of Cystic Fibrosis","volume":"57","author":"Ramalho","year":"2021","journal-title":"Eur. Respir. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10424\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:04:51Z","timestamp":1760112291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10424"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,27]]},"references-count":23,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910424"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910424","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,27]]}}}