ArticleJournal of medical genetics2015
Differential increases of specific FMR1 mRNA isoforms in premutation carriers.
Article in Journal of medical genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Novel p.Arg534del Mutation and MTHFR C667T Polymorphism in Fragile X Syndrome (FXS) With Autism Spectrum Phenotype: A Case Report.Case reports in genetics · 2025Article
- Beyond the Synapse:International journal of molecular sciences · 2024Review
- Review
- CNS-dominant human FMRP isoform rescues seizures, fear, and sleep abnormalities in Fmr1-KO mice.JCI insight · 2023Article
- Clinical implications of somatic allele expansion in female FMR1 premutation carriers.Scientific reports · 2023Article
- Structure and Alternative Splicing of the Antisense FMR1 (ASFMR1) Gene.Molecular neurobiology · 2023Article
- Gene therapy using human FMRP isoforms driven by the humanMolecular therapy. Methods & clinical development · 2022Article
- Autism spectrum disorder in the fragile X premutation state: possible mechanisms and implications.Journal of neurology · 2022Review
- Uncovering Essential Tremor Genetics: The Promise of Long-Read Sequencing.Frontiers in neurology · 2022Review
- Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity.Molecular therapy. Methods & clinical development · 2021Article
- Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes.International journal of molecular sciences · 2021Review
- The RNA-binding fragile-X mental retardation protein and its role beyond the brain.Biophysical reviews · 2020Review
- FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS).Scientific reports · 2020Article
- Further identification of a 140bp sequence from amid intron 9 of human FMR1 gene as a new exon.BMC genetics · 2020Article
- The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome.Brain sciences · 2019Review
- Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models.Frontiers in molecular neuroscience · 2019Review
- Deciphering highly similar multigene family transcripts from Iso-Seq data with IsoCon.Nature communications · 2018Article
- Use of human-derived stem cells to create a novel, in vitro model designed to explore FMR1 CGG repeat instability amongst female premutation carriers.Journal of assisted reproduction and genetics · 2018Article
- Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics.Nucleic acids research · 2018Review
- Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundOver 40% of male and ∼16% of female carriers of a premutation FMR1 allele (55-200 CGG repeats) will develop fragile X-associated tremor/ataxia syndrome, an adult onset neurodegenerative disorder, while about 20% of female carriers will develop fragile X-associated primary ovarian insufficiency. Marked elevation in FMR1 mRNA transcript levels has been observed with premutation alleles, and RNA toxicity due to increased mRNA levels is the leading molecular mechanism proposed for these disorders. However, although the FMR1 gene undergoes alternative splicing, it is unknown whether all or only some of the isoforms are overexpressed in premutation carriers and which isoforms may contribute to the premutation pathology.
methodsTo address this question, we have applied a long-read sequencing approach using single-molecule real-time (SMRT) sequencing and qRT-PCR.
resultsOur SMRT sequencing analysis performed on peripheral blood mononuclear cells, fibroblasts and brain tissue samples derived from premutation carriers and controls revealed the existence of 16 isoforms of 24 predicted variants. Although the relative abundance of all mRNA isoforms was significantly increased in the premutation group, as expected based on the bulk increase in mRNA levels, there was a disproportionate (fourfold to sixfold) increase, relative to the overall increase in mRNA, in the abundance of isoforms spliced at both exons 12 and 14, specifically Iso10 and Iso10b, containing the complete exon 15 and differing only in splicing in exon 17.
conclusionsThese findings suggest that RNA toxicity may arise from a relative increase of all FMR1 mRNA isoforms. Interestingly, the Iso10 and Iso10b mRNA isoforms, lacking the C-terminal functional sites for fragile X mental retardation protein function, are the most increased in premutation carriers relative to normal, suggesting a functional relevance in the pathology of FMR1-associated disorders.
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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.