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Hum Mol Genet. 2015 Jun 15;24(12):3457-71. doi: 10.1093/hmg/ddv096. Epub 2015 Mar 26.

Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells.

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  • 1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK, Faculdade de Medicina, Universidade de Lisboa, Lisboa 1649-028, Portugal and.
  • 2Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 3Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK,


Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA-FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA-FXN locus at single-cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur.

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