ArticleHuman genetics2007
The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model.
Article in Human genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 71 citations in OpenAlex.
- Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.Brain : a journal of neurology · 2025Article
- The Regulation of the Disease-Causing GeneCells · 2024Review
- Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers.Nucleic acids research · 2023Article
- A new FRDA mouse model [Frontiers in neuroscience · 2023Article
- Review
- DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.Scientific reports · 2022Article
- Perspectives on current models of Friedreich's ataxia.Frontiers in cell and developmental biology · 2022Article
- Replication-independent instability of Friedreich's ataxia GAA repeats during chronological aging.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington's Disease.Journal of Huntington's disease · 2021Review
- Review
- Replication stalling and DNA microsatellite instability.Biophysical chemistry · 2017Review
- Article
- 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.Cell death & disease · 2016Article
- The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015Review
- A novel GAA-repeat-expansion-based mouse model of Friedreich's ataxia.Disease models & mechanisms · 2015Article
- The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype.Acta neuropathologica · 2014Review
- Article
- Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models.PloS one · 2014Article
- Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.PloS one · 2014Article
- Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia.Disease models & mechanisms · 2013Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence. Patients have progressive neurodegeneration of the dorsal root ganglia (DRG) and in later stages the cerebellum may be involved. The expanded GAA-TR sequence is unstable in somatic cells in vivo, and although the mechanism of instability remains unknown, we hypothesized that age-dependent and tissue-specific somatic instability may be a determinant of the progressive pathology involving DRG and cerebellum. We show that transgenic mice containing the expanded GAA-TR sequence (190 or 82 triplets) in the context of the human FXN locus show tissue-specific and age-dependent somatic instability that is compatible with this hypothesis. Small pool PCR analysis, which allows quantitative analysis of repeat instability by assaying individual transgenes in vivo, showed age-dependent expansions specifically in the cerebellum and DRG. The (GAA)(190) allele showed some instability by 2 months, progressed at about 0.3-0.4 triplets per week, resulting in a significant number of expansions by 12 months. Repeat length was found to determine the age of onset of somatic instability, and the rate and magnitude of mutation. Given the low level of cerebellar instability seen by others in multiple transgenic mice with expanded CAG/CTG repeats, our data indicate that somatic instability of the GAA-TR sequence is likely mediated by unique tissue-specific factors. This mouse model will serve as a useful tool to delineate the mechanism(s) of disease-specific somatic instability in FRDA.
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