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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

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, howeve...

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Autores principales: Sondo, Elvira, Cresta, Federico, Pastorino, Cristina, Tomati, Valeria, Capurro, Valeria, Pesce, Emanuela, Lena, Mariateresa, Iacomino, Michele, Baffico, Ave Maria, Coviello, Domenico, Bandiera, Tiziano, Zara, Federico, Galietta, Luis J. V., Bocciardi, Renata, Castellani, Carlo, Pedemonte, Nicoletta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8952007/
https://www.ncbi.nlm.nih.gov/pubmed/35328596
http://dx.doi.org/10.3390/ijms23063175
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author Sondo, Elvira
Cresta, Federico
Pastorino, Cristina
Tomati, Valeria
Capurro, Valeria
Pesce, Emanuela
Lena, Mariateresa
Iacomino, Michele
Baffico, Ave Maria
Coviello, Domenico
Bandiera, Tiziano
Zara, Federico
Galietta, Luis J. V.
Bocciardi, Renata
Castellani, Carlo
Pedemonte, Nicoletta
author_facet Sondo, Elvira
Cresta, Federico
Pastorino, Cristina
Tomati, Valeria
Capurro, Valeria
Pesce, Emanuela
Lena, Mariateresa
Iacomino, Michele
Baffico, Ave Maria
Coviello, Domenico
Bandiera, Tiziano
Zara, Federico
Galietta, Luis J. V.
Bocciardi, Renata
Castellani, Carlo
Pedemonte, Nicoletta
author_sort Sondo, Elvira
collection PubMed
description Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.
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spelling pubmed-89520072022-03-26 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 Sondo, Elvira Cresta, Federico Pastorino, Cristina Tomati, Valeria Capurro, Valeria Pesce, Emanuela Lena, Mariateresa Iacomino, Michele Baffico, Ave Maria Coviello, Domenico Bandiera, Tiziano Zara, Federico Galietta, Luis J. V. Bocciardi, Renata Castellani, Carlo Pedemonte, Nicoletta Int J Mol Sci Article Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators. MDPI 2022-03-15 /pmc/articles/PMC8952007/ /pubmed/35328596 http://dx.doi.org/10.3390/ijms23063175 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sondo, Elvira
Cresta, Federico
Pastorino, Cristina
Tomati, Valeria
Capurro, Valeria
Pesce, Emanuela
Lena, Mariateresa
Iacomino, Michele
Baffico, Ave Maria
Coviello, Domenico
Bandiera, Tiziano
Zara, Federico
Galietta, Luis J. V.
Bocciardi, Renata
Castellani, Carlo
Pedemonte, Nicoletta
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8952007/
https://www.ncbi.nlm.nih.gov/pubmed/35328596
http://dx.doi.org/10.3390/ijms23063175
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