title: Genetic variations creating microRNA target sites in the FXN 3'-UTR affect frataxin expression in Friedreich ataxia.
abstract: Friedreich's ataxia (FRDA) is a severe neurodegenerative disease caused by GAA repeat expansion within the first intron of the frataxin gene. It has been suggested that the repeat is responsible for the disease severity due to impaired transcription thereby reducing expression of the protein. However, genotype-phenotype correlation is imperfect, and the influence of other gene regions of the frataxin gene is unknown. We hypothesized that FRDA patients may harbor specific regulatory variants in the 3'-UTR. We sequenced the 3'-UTR region of the frataxin gene in a cohort of 57 FRDA individuals and 58 controls. Seven single nucleotide polymorphisms (SNPs) out of 19 were polymorphic in our case-control sample. These SNPs defined several haplotypes with one reaching 89% of homozygosity in patients versus 24% in controls. In another cohort of 47 FRDA Reunionese patients, 94% patients were found to be homozygous for this haplotype. We found that this FRDA 3'-UTR conferred a 1.2-fold decrease in the expression of a reporter gene versus the alternative haplotype configuration. We established that differential targeting by miRNA could account for this functional variability. We specifically demonstrated the involvement of miR-124 (i.e hsa-mir-124-3p) in the down-regulation of FRDA-3'-UTR. Our results suggest for the first time that post-transcriptional regulation of frataxin occurs through the 3'-UTR and involves miRNA targeting. We propose that the involvement of miRNAs in a FRDA-specific regulation of frataxin may provide a rationale to increase residual levels of frataxin through miRNA-inhibitory molecules.
authors: INSERM U781 Hôpital Necker-Enfants Malades, Université Paris Descartes-Sorbonne Cité, Institut Imagine, Paris, France.
authors: Simonetta
authors: S
authors: Bandiera
authors: François
authors: F
authors: Cartault
authors: Anne-Sophie
authors: AS
authors: Jannot
authors: Elie
authors: E
authors: Hatem
authors: Muriel
authors: M
authors: Girard
authors: Laila
authors: L
authors: Rifai
authors: Clemence
authors: C
authors: Loiseau
authors: Arnold
authors: A
authors: Munnich
authors: Stanislas
authors: S
authors: Lyonnet
authors: Alexandra
authors: A
authors: Henrion-Caude
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D005621:Friedreich Ataxia / Q000235:genetics*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D019680:Trinucleotide Repeat Expansion; D000096923:Frataxin
chemical_list: D020413:3' Untranslated Regions; D033862:Iron-Binding Proteins; D035683:MicroRNAs; D000096923:Frataxin
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