Genetic variations creating microRNA target sites in the FXN 3'-UTR affect frataxin expression in Friedreich ataxia.

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.