ArticleAnnals of neurology2016
Repeat-associated non-AUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome.
Article in Annals of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 67 citations in OpenAlex.
- Current biomarker development in myotonic dystrophies.Journal of neurology · 2026Review
- The role of FMR1 mRNA structure on the efficiency of non-canonical translation of toxic polyglycine protein.Nucleic acids research · 2026Article
- MBNL proteins in health, disease, and therapeutic applications.Nucleic acids research · 2026Review
- IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats.Nature communications · 2025Article
- Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.Nucleic acids research · 2024Article
- Mitochondrial Dysfunction in Repeat Expansion Diseases.Antioxidants (Basel, Switzerland) · 2023Review
- Dissecting the roles of EIF4G homologs reveals DAP5 as a modifier of CGG repeat-associated toxicity in a Drosophila model of FXTAS.Neurobiology of disease · 2023Article
- Between Order and Chaos: Understanding the Mechanism and Pathology of RAN Translation.Biological & pharmaceutical bulletin · 2023Review
- The polyG diseases: a new disease entity.Acta neuropathologica communications · 2022Review
- Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions.Nature reviews. Neurology · 2022Review
- Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A Gender Perspective.Journal of clinical medicine · 2022Review
- RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies.Current opinion in neurobiology · 2022Review
- Clinical and mechanism advances of neuronal intranuclear inclusion disease.Frontiers in aging neuroscience · 2022Review
- Measuring Repeat-Associated Non-AUG (RAN) Translation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- GC-rich repeat expansions: associated disorders and mechanisms.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2021Article
- SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity.EMBO molecular medicine · 2021Article
- Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation.Nucleic acids research · 2021Article
- Molecular mechanisms underlying nucleotide repeat expansion disorders.Nature reviews. Molecular cell biology · 2021Review
- (Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology inInternational journal of molecular sciences · 2021Review
- Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
objectiveRepeat-associated non-AUG (RAN) translation drives production of toxic proteins from pathogenic repeat sequences in multiple untreatable neurodegenerative disorders. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such condition, resulting from a CGG trinucleotide repeat expansion in the 5' leader sequence of the FMR1 gene. RAN proteins from the CGG repeat accumulate in ubiquitinated inclusions in FXTAS patient brains and elicit toxicity. In addition to the CGG repeat, an antisense mRNA containing a CCG repeat is also transcribed from the FMR1 locus. We evaluated whether this antisense CCG repeat supports RAN translation and contributes to pathology in FXTAS patients.
methodsWe generated a series of CCG RAN translation-specific reporters and utilized them to measure RAN translation from CCG repeats in multiple reading frames in transfected cells. We also developed antibodies against predicted CCG RAN proteins and used immunohistochemistry and immunofluorescence on FXTAS patient tissues to measure their accumulation and distribution.
resultsRAN translation from CCG repeats is supported in all 3 potential reading frames, generating polyproline, polyarginine, and polyalanine proteins, respectively. Their production occurs whether or not the natural AUG start upstream of the repeat in the proline reading frame is present. All 3 frames show greater translation at larger repeat sizes. Antibodies targeted to the antisense FMR polyproline and polyalanine proteins selectively stain nuclear and cytoplasmic aggregates in FXTAS patients and colocalize with ubiquitinated neuronal inclusions.
interpretationRAN translation from antisense CCG repeats generates novel proteins that accumulate in ubiquitinated inclusions in FXTAS patients. Ann Neurol 2016;80:871-881.
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