ArticleThe Journal of biological chemistry2010
A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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115 citing papers in PubMed, 200 citations in OpenAlex.
- Synonymous variants in IRX4 and their association with congenital heart disease: an in-silico functional assessment.Molecular biology reports · 2026Article
- Large variations in total and allele-specific transcript expression in a disease mutation-independent manner.Scientific reports · 2026Article
- Serine tRNAs compete to regulate the mRNA translation of serine-sensitive codons.Science advances · 2025Article
- Functional synonymous mutations and their evolutionary consequences.Nature reviews. Genetics · 2025Review
- Whole exon screening of SLC2A4 gene and the association of rs5435 with type 2 diabetes in a Bangladeshi case-control study.Journal, genetic engineering & biotechnology · 2025Article
- RNA editing generates mRNA isoforms with distinct stabilities that may expand the thermal tolerance of mRNA and proteins inZoological research · 2025Article
- In Silico Prioritization of STAT1 3' UTR SNPs Identifies rs190542524 as a miRNA-Linked Variant with Potential Oncogenic Impact.Non-coding RNA · 2025Article
- Uncovering codon usage patterns during murine embryogenesis and tissue-specific developmental diseases.Frontiers in genetics · 2025Article
- Ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Ribosomal Frameshifting Selectively Modulates the Assembly, Function, and Pharmacological Rescue of a Misfolded CFTR Variant.bioRxiv : the preprint server for biology · 2024Article
- The Effects of Codon Usage on Protein Structure and Folding.Annual review of biophysics · 2024Review
- Molecular Mechanisms and the Significance of Synonymous Mutations.Biomolecules · 2024Review
- In silico methods for predicting functional synonymous variants.Genome biology · 2023Review
- Features of CFTR mRNA and implications for therapeutics development.Frontiers in genetics · 2023Review
- Exploring the influence of DNA methylation and single nucleotide polymorphisms of theFrontiers in genetics · 2023Article
- A minimal role for synonymous variation in human disease.American journal of human genetics · 2022Article
- Tetra-primers ARMS-PCR Based Association Analyses of Synonymous and Intronic Variants in the ADAM12 Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study.Biochemical genetics · 2022Article
- Structural, functional, and immunogenicity implications of F9 gene recoding.Blood advances · 2022Article
- Codon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon.Nature communications · 2022Article
- Experimental demonstration and pan-structurome prediction of climate-associated riboSNitches in Arabidopsis.Genome biology · 2022Article
55 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Recent advances in our understanding of translational dynamics indicate that codon usage and mRNA secondary structure influence translation and protein folding. The most frequent cause of cystic fibrosis (CF) is the deletion of three nucleotides (CTT) from the cystic fibrosis transmembrane conductance regulator (CFTR) gene that includes the last cytosine (C) of isoleucine 507 (Ile507ATC) and the two thymidines (T) of phenylalanine 508 (Phe508TTT) codons. The consequences of the deletion are the loss of phenylalanine at the 508 position of the CFTR protein (DeltaF508), a synonymous codon change for isoleucine 507 (Ile507ATT), and protein misfolding. Here we demonstrate that the DeltaF508 mutation alters the secondary structure of the CFTR mRNA. Molecular modeling predicts and RNase assays support the presence of two enlarged single stranded loops in the DeltaF508 CFTR mRNA in the vicinity of the mutation. The consequence of DeltaF508 CFTR mRNA "misfolding" is decreased translational rate. A synonymous single nucleotide variant of the DeltaF508 CFTR (Ile507ATC), that could exist naturally if Phe-508 was encoded by TTC, has wild type-like mRNA structure, and enhanced expression levels when compared with native DeltaF508 CFTR. Because CFTR folding is predominantly cotranslational, changes in translational dynamics may promote DeltaF508 CFTR misfolding. Therefore, we propose that mRNA "misfolding" contributes to DeltaF508 CFTR protein misfolding and consequently to the severity of the human DeltaF508 phenotype. Our studies suggest that in addition to modifier genes, SNPs may also contribute to the differences observed in the symptoms of various DeltaF508 homozygous CF patients.
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