Journal
NUCLEIC ACIDS RESEARCH
Volume 36, Issue 19, Pages 6056-6065Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkn604
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Funding
- National Institutes of Health [ES11347, R21NS055781]
- Friedreich's Ataxia Research Alliance
- Seek a Miracle
- Robert A. Welch Foundation
- National Ataxia Foundation
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Friedreich ataxia (FRDA) is caused by hyperexpansion of GAATTC repeats located in the first intron of the FXN gene, which inhibits transcription leading to the deficiency of frataxin. The FXN gene is an excellent target for therapeutic intervention since (i) 98 of patients carry the same type of mutation, (ii) the mutation is intronic, thus leaving the FXN coding sequence unaffected and (iii) heterozygous GAATTC expansion carriers with 50 decrease of the frataxin are asymptomatic. The discovery of therapeutic strategies for FRDA is hampered by a lack of appropriate molecular models of the disease. Herein, we present the development of a new cell line as a molecular model of FRDA by inserting 560 GAATTC repeats into an intron of a GFP reporter minigene. The GFP(GAATTC)(560) minigene recapitulates the molecular hallmarks of the mutated FXN gene, i.e. inhibition of transcription of the reporter gene, decreased levels of the reporter protein and hypoacetylation and hypermethylation of histones in the vicinity of the repeats. Additionally, selected histone deacetylase inhibitors, known to stimulate the FXN gene expression, increase the expression of the GFP(GAATTC)(560) reporter. This FRDA model can be adapted to high-throughput analyses in a search for new therapeutics for the disease.
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