ArticlePLoS genetics2018
Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism.Pharmaceutical biology · 2025Article
- Elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis harbouring twoEClinicalMedicine · 2025Article
- Organoid-on-a-chip (OrgOC): Advancing cystic fibrosis research.Materials today. Bio · 2025Review
- An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.Nucleic acids research · 2025Article
- RNA splicing: Novel star in pulmonary diseases with a treatment perspective.Acta pharmaceutica Sinica. B · 2025Review
- A W1282X cystic fibrosis mouse allows the study of pharmacological and gene-editing therapeutics to restore CFTR function.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2025Article
- Systematic deletion of symmetricalNAR molecular medicine · 2024Article
- A New Frontier in Cystic Fibrosis Pathophysiology: How and When Clock Genes Can Affect the Inflammatory/Immune Response in a Genetic Disease Model.Current issues in molecular biology · 2024Review
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- Readthrough-induced misincorporated amino acid ratios guide mutant-specific therapeutic approaches for two CFTR nonsense mutations.Frontiers in pharmacology · 2024Article
- Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X.Human molecular genetics · 2023Article
- Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells.Molecular therapy. Nucleic acids · 2023Article
- Q1291H-CFTR molecular dynamics simulations andFrontiers in molecular biosciences · 2023Article
- Features of CFTR mRNA and implications for therapeutics development.Frontiers in genetics · 2023Review
- Downstream Alternate Start Site Allows N-Terminal Nonsense Variants to Escape NMD and Results in Functional Recovery by Readthrough and Modulator Combination.Journal of personalized medicine · 2022Article
- Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis.Journal of personalized medicine · 2022Review
- Splicing mutations in the CFTR gene as therapeutic targets.Gene therapy · 2022Review
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway.Nature communications · 2022Article
- Article
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function <1% (n = 5)) and Group B (normal mRNA, immature protein, function <1% (n = 10)) variants were unresponsive to modulator treatment. However, Group C (normal mRNA, mature (fully glycosylated) protein, function >1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic 'nulls' as some may allow generation of protein that can be targeted to achieve clinical benefit.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.