GAA repeat instability in Friedreich ataxia YAC transgenic mice

Al-Mahdawi, Sahar; Pinto, Ricardo Mouro; Ruddle, Piers; Carroll, Christopher J.; Webster, Zoë; Pook, Mark A.

doi:10.1016/j.ygeno.2004.04.003

Cited by 85 publications

(96 citation statements)

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“…The observation of somatic instability in the central nervous system of YG8 and YG22 mice was previously noted as increased "smearing" upon electrophoresis of PCR ampliWed products (Al-Mahdawi et al 2004).…”

Section: Discussionmentioning

confidence: 93%

“…To investigate this we used two preexisting transgenic mouse lines with expanded GAA-TR alleles in the context of the human FXN locus (YG8 and YG22). They were previously reported to have germline instability, and conventional PCR analysis revealed increased "smearing" of the GAA-TR sequence using cerebellar DNA (Al-Mahdawi et al 2004). DRG was not analyzed.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2006

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Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence. This expanded GAA-TR sequence is unstable in somatic cells of FRDA patients, showing age-dependent expansions in dorsal root ganglia (DRG), the tissue where pathology occurs earliest and is most significant. This is thought to be the basis for the progressive, tissue-specific pathology seen in FRDA, but the mechanism(s) for this somatic instability is unknown. 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 mimics the human condition. Small pool PCR analysis, which allows quantitative analysis of 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/week, resulting in a significant number of expansions by 12 months. Repeat length determined the age of onset of somatic instability, and the rate and magnitude of expansion.Whereas the GAA-TR was unstable in the context of the human FXN locus, pure GAA-TR sequences at other genetic loci in the human and murine genomes showed no instability. These data indicate that somatic instability of the GAA-TR sequence in the human FXN gene is determined by a combination of unique cis and trans-acting factors.This mouse model will serve as a useful tool to delineate the mechanism(s) of diseasespecific somatic instability in FRDA.3

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…However, a somatic expansion bias exists within post-mitotic neurons of the spinal cord in FRDA patients (29) and mouse models (44,45). To investigate whether a lack of replication contributed to this bias, we performed parallel experiments with both dividing and non-dividing primary FRDA patient fibroblasts.…”

Section: Ectopic Expression Of Msh3 Is Sufficient To Induce Gaa⅐ttc Rmentioning

confidence: 99%

DNA Mismatch Repair Complex MutSβ Promotes GAA·TTC Repeat Expansion in Human Cells

Halabi

Ditch²,

Wang

et al. 2012

Journal of Biological Chemistry

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Background: Friedreich ataxia (FRDA) is a progressive, debilitating and lethal disease caused by GAA⅐TTC repeat expansion. Results: Expression of mismatch repair complex MutS␤, particularly the MSH3 subunit, is necessary for GAA⅐TTC repeat expansion in model cells and FRDA patient fibroblasts. Conclusion: MutS␤ promotes GAA⅐TTC expansion in FRDA. Significance: MSH3 may be a potential therapeutic target for slowing GAA⅐TTC expansion.

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“…Mammalian cell models using a plasmid construct with GAA⅐TTC triplet repeats have shown that the repeat expansions are transcription-, replication-, and position-dependent (10 -12). In addition, mouse models with expanded GAA⅐TTC triplet repeats show somatic instability in different tissues (13)(14)(15). These systems differ substantially from humans and from each other in terms of DNA replication rate, the cell type in which GAA⅐TTC triplet-repeat expansion occurs, and chromatin structure.…”

mentioning

confidence: 99%

Role of Mismatch Repair Enzymes in GAA·TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells

Campau

Soragni

et al. 2012

Journal of Biological Chemistry

103

129

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Background: Friedreich ataxia is caused by a GAA⅐TTC triplet-repeat expansion in the first intron of the FXN gene. Results: Expansion of the repeats is observed in induced pluripotent stem cells (iPSCs) and can be blocked with either shRNAs to mismatch repair enzymes or small molecules targeting the repeats. Conclusion: MutS␣ and MutS␤ are involved in repeat expansion. Significance: iPSCs provide a model system for studying triplet-repeat expansion.

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GAA repeat instability in Friedreich ataxia YAC transgenic mice

Cited by 85 publications

References 50 publications

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

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

DNA Mismatch Repair Complex MutSβ Promotes GAA·TTC Repeat Expansion in Human Cells

Role of Mismatch Repair Enzymes in GAA·TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells

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