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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-8952007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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