ArticleProceedings of the National Academy of Sciences of the United States of America2004
A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00037778 (Genetic Modifiers of Cystic Fibrosis), which is not on this map. Cited by 78 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Genetic Modifiers of Cystic Fibrosis: Sibling Study
Who cites it
78 citing papers in PubMed, 161 citations in OpenAlex.
- Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.Nature aging · 2026Article
- The contribution of short tandem repeats to splicing variation in the human cortex.bioRxiv : the preprint server for biology · 2026Article
- A Statistical Framework to Infer the Mutation Model of Tandem Repeat Variants.bioRxiv : the preprint server for biology · 2026Article
- The structure, folding kinetics, and dynamics of long poly(UG) RNA.Nucleic acids research · 2025Article
- Intact spermatogenesis in an azoospermic patient with AZFa (sY84 and sY86) microdeletion and a homozygous TG12-5T variant in CFTR.Basic and clinical andrology · 2025Article
- TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.Acta neuropathologica · 2024Article
- Short Tandem Repeats in the era of next-generation sequencing: from historical loci to population databases.European journal of human genetics : EJHG · 2024Review
- Accurate and Automated Genotyping of theInternational journal of molecular sciences · 2024Article
- High frequency of germline variants in CFTR identified in PDAC patients enrolled in an expanded panel multi-gene panel testing program.HPB : the official journal of the International Hepato Pancreato Biliary Association · 2024Article
- Increased prevalence ofHeliyon · 2024Article
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- Solution Structure of Poly(UG) RNA.Journal of molecular biology · 2023Article
- Polymorphic short tandem repeats make widespread contributions to blood and serum traits.Cell genomics · 2023Article
- Whole exome sequencing reveal 83 novel Mendelian disorders carrier P/LP variants in Chinese adult patients.Journal of human genetics · 2023Article
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- Bioinformatics pipeline to guide post-GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
- G-QINDER Tool: Bioinformatically Predicted Formation of Different Four-Stranded DNA Motifs from (GT)International journal of molecular sciences · 2023Article
- Profiling human pathogenic repeat expansion regions by synergistic and multi-level impacts on molecular connections.Human genetics · 2023Article
- Article
- Features of CFTR mRNA and implications for therapeutics development.Frontiers in genetics · 2023Review
18 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Dinucleotide repeats are ubiquitous features of eukaryotic genomes that are not generally considered to have functional roles in gene expression. However, the highly variable nature of dinucleotide repeats makes them particularly interesting candidates for modifiers of RNA splicing when they are found near splicing signals. An example of a variable dinucleotide repeat that affects splicing is a TG repeat located in the splice acceptor of exon 9 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens or nonclassic cystic fibrosis. Using a CFTR minigene system, we studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Replacement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacements of the TG tract with sequences that can self-base-pair suggested that the formation of an RNA secondary structure was associated with efficient splicing. However, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution with TA repeats of differing length confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Taken together, these data indicate that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype.
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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.