ArticlePLoS genetics2009
Progressive GAA.TTC repeat expansion in human cell lines.
Article in PLoS genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- Epigenetic therapy for Friedreich ataxia.Annals of neurology · 2014Trial
- Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice.Nature genetics · 2025Article
- MSH2 is not required for either maintenance of DNA methylation or repeat contraction at the FMR1 locus in fragile X syndrome or the FXN locus in Friedreich's ataxia.Epigenetics & chromatin · 2025Article
- Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.Brain : a journal of neurology · 2025Article
- Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease.NAR molecular medicine · 2024Article
- Review
- Suppression of trinucleotide repeat expansion in spermatogenic cells in Huntington's disease.Journal of assisted reproduction and genetics · 2022Article
- Review
- 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
- On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability.The Journal of biological chemistry · 2020Review
- Prospective natural history study ofNeurology · 2019Article
- Progress in understanding Friedreich's ataxia using human induced pluripotent stem cells.Expert opinion on orphan drugs · 2019Article
- R-loops: targets for nuclease cleavage and repeat instability.Current genetics · 2018Review
- GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one.Nucleic acids research · 2018Article
- RNA-DNA hybrids promote the expansion of Friedreich's ataxia (GAA)n repeats via break-induced replication.Nucleic acids research · 2018Article
- Timing of Expansion of Fragile X Premutation Alleles During Intergenerational Transmission in a Mouse Model of the Fragile X-Related Disorders.Frontiers in genetics · 2018Article
- The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion.PLoS genetics · 2016Article
- Translating HDAC inhibitors in Friedreich's ataxia.Expert opinion on orphan drugs · 2016Article
- Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus.Human molecular genetics · 2015Article
- Excision of Expanded GAA Repeats Alleviates the Molecular Phenotype of Friedreich's Ataxia.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Article
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Authors and funding
4 authors.
Funding
Abstract
Trinucleotide repeat expansion is the genetic basis for a sizeable group of inherited neurological and neuromuscular disorders. Friedreich ataxia (FRDA) is a relentlessly progressive neurodegenerative disorder caused by GAA.TTC repeat expansion in the first intron of the FXN gene. The expanded repeat reduces FXN mRNA expression and the length of the repeat tract is proportional to disease severity. Somatic expansion of the GAA.TTC repeat sequence in disease-relevant tissues is thought to contribute to the progression of disease severity during patient aging. Previous models of GAA.TTC instability have not been able to produce substantial levels of expansion within an experimentally useful time frame, which has limited our understanding of the molecular basis for this expansion. Here, we present a novel model for studying GAA.TTC expansion in human cells. In our model system, uninterrupted GAA.TTC repeat sequences display high levels of genomic instability, with an overall tendency towards progressive expansion. Using this model, we characterize the relationship between repeat length and expansion. We identify the interval between 88 and 176 repeats as being an important length threshold where expansion rates dramatically increase. We show that expansion levels are affected by both the purity and orientation of the repeat tract within the genomic context. We further demonstrate that GAA.TTC expansion in our model is independent of cell division. Using unique reporter constructs, we identify transcription through the repeat tract as a major contributor to GAA.TTC expansion. Our findings provide novel insight into the mechanisms responsible for GAA.TTC expansion in human cells.
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