Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 variant

This study investigates the molecular and functional consequences of rare CFTR variants, particularly focusing on the complex allele [186-13C > G; 1898 + 3A > G] and the CFTRdele2ins182 rearrangement. Using patient-derived nasal epithelial cells, the research characterized the transcripts produced by these variants, revealing that CFTRdele2ins182, previously considered a null allele, generates alternative mRNA isoforms, one of which potentially encodes a partially functional CFTR protein. Functional assays in both heterologous and patient-derived cell models explored the impact of CFTR modulators on these variant proteins. While some rescue of CFTR activity was observed with specific modulator combinations in certain variants, the study highlights the complexity of genotype-phenotype correlations in CF and emphasizes the importance of personalized functional characterization of rare CFTR variants to guide therapeutic strategies. The findings suggest that even variants thought to be null alleles may produce proteins with residual function, opening avenues for developing targeted therapies for a broader range of CF patients.

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Publication Details

Journal
PLoS ONE
Published
2025-09-16
DOI
https://doi.org/10.1371/journal.pone.0330974
Citations
1
Primary Topic
Cystic Fibrosis Research Advances
Type
article
Field-Weighted Citation Impact
1.52
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article

Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 variant

Renata Bocciardi, Francesco Blasi, Marco Di Duca, Emanuela Pesce et al.
1 citations
PLoS ONE
Cystic Fibrosis Research Advances
1.52
article

Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 variant

Renata Bocciardi, Francesco Blasi, Marco Di Duca, Emanuela Pesce, Cristina Pastorino, Vito Terlizzi, Nicoletta Pedemonte, Federico Zara, Andrea Gramegna, Serena Cappato, Mariateresa Lena, Valeria Tomati, Valeria Capurro, Carlo Castellani, Ludovica Menta
article en
1 citations

Abstract

This study investigates the molecular and functional consequences of rare CFTR variants, particularly focusing on the complex allele [186-13C > G; 1898 + 3A > G] and the CFTRdele2ins182 rearrangement. Using patient-derived nasal epithelial cells, the research characterized the transcripts produced by these variants, revealing that CFTRdele2ins182, previously considered a null allele, generates alternative mRNA isoforms, one of which potentially encodes a partially functional CFTR protein. Functional assays in both heterologous and patient-derived cell models explored the impact of CFTR modulators on these variant proteins. While some rescue of CFTR activity was observed with specific modulator combinations in certain variants, the study highlights the complexity of genotype-phenotype correlations in CF and emphasizes the importance of personalized functional characterization of rare CFTR variants to guide therapeutic strategies. The findings suggest that even variants thought to be null alleles may produce proteins with residual function, opening avenues for developing targeted therapies for a broader range of CF patients.

PLoS ONEVol. 20(9)
Neurosciences Institute (US), University of Milan (IT), Istituto Giannina Gaslini (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Meyer Children's Hospital (IT), Center for Neurosciences (US), University of Genoa (IT)
Openalex Percentile: Top 14%
Cystic Fibrosis Research Advances
1.52
DOIOpen Access PDFOpenAlex
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