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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 <jats:italic>CFTR<\/jats:italic> 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0330974","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T17:29:28Z","timestamp":1758043768000},"page":"e0330974","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 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