ArticleAmerican journal of human genetics2008
Influence of Friedreich ataxia GAA noncoding repeat expansions on pre-mRNA processing.
Article in American journal of human genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 52 citations in OpenAlex.
- SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study.Journal of experimental & clinical cancer research : CR · 2014Trial
- Emerging antioxidant therapies in Friedreich's ataxia.Frontiers in pharmacology · 2024Review
- Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Genome-wide association study identified ATP6V1H locus influencing cerebrospinal fluid BACE activity.BMC medical genetics · 2018Article
- Intron retention induced by microsatellite expansions as a disease biomarker.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- RNA Editing and Retrotransposons in Neurology.Frontiers in molecular neuroscience · 2018Review
- Functional Mechanisms of Microsatellite DNA in Eukaryotic Genomes.Genome biology and evolution · 2017Review
- RNA biology of disease-associated microsatellite repeat expansions.Acta neuropathologica communications · 2017Review
- MiRNA-145 Regulates the Development of Congenital Heart Disease Through Targeting FXN.Pediatric cardiology · 2016Article
- Translating HDAC inhibitors in Friedreich's ataxia.Expert opinion on orphan drugs · 2016Article
- The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015Review
- Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck.European journal of cancer (Oxford, England : 1990) · 2014Article
- Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia.Journal of neurochemistry · 2013Review
- Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia.Journal of child neurology · 2012Review
- Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia.Biochimica et biophysica acta · 2012Review
- Is Friedreich ataxia an epigenetic disorder?Clinical epigenetics · 2012Article
- Article
- Polymorphisms of XPG/ERCC5 and risk of squamous cell carcinoma of the head and neck.Pharmacogenetics and genomics · 2012Article
- Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs.The pharmacogenomics journal · 2011Article
- Intron cleavage affects processing of alternatively spliced transcripts.RNA (New York, N.Y.) · 2011Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The intronic GAA repeat expansion in the frataxin (FXN) gene causes the hereditary neurodegenerative disorder Friedreich ataxia. Although it is generally believed that GAA repeats block transcription elongation, direct proof in eukaryotic systems is lacking. We tested in hybrid minigenes the effect of GAA and TTC repeats on nascent transcription and pre-mRNA processing. Unexpectedly, disease-causing GAA(100) repeats did not affect transcriptional elongation in a nuclear HeLa Run On assay, nor did they affect pre-mRNA transcript abundance. However, they did result in a complex defect in pre-mRNA processing. The insertion of GAA but not TTC repeats downstream of reporter exons resulted in their partial or complete exclusion from the mature mRNAs and in the generation of a variety of aberrant splicing products. This effect of GAA repeats was observed to be position and context dependent; their insertion at different distances from the reporter exons had a variable effect on splice-site selection. In addition, GAA repeats bind to a multitude of different splicing factors and induced the accumulation of an upstream pre-mRNA splicing intermediate, which is not turned over into mature mRNA. When embedded in the homologous frataxin minigene system, the GAA repeats did not affect the pre-mRNA transcript abundance but did significantly reduce the splicing efficiency of the first intron. These data indicate an association between GAA noncoding repeats and aberrant pre-mRNA processing because binding of transcribed GAA repeats to a multitude of trans-acting splicing factors can interfere with normal turnover of intronic RNA and thus lead to its degradation and a lower abundance of mature mRNA.
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