Genetic Variation in ATXN3 (Ataxin-3) 3′UTR: Insights into the Downstream Regulatory Elements of the Causative Gene of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3

Untranslated regions are involved in the regulation of transcriptional and post-transcriptional processes. Characterization of these regions remains poorly explored for ATXN3, the causative gene of Machado-Joseph disease (MJD). Although a few genetic modifiers have been identified for MJD age at onset (AO), they only explain a small fraction of the AO variance. Our aim was to analyse variation at the 3 ' UTR of ATXN3 in MJD patients, analyse its impact on AO and attempt to build haplotypes that might discriminate between normal and expanded alleles. After assessing ATXN3 3 ' UTR variants in molecularly confirmed MJD patients, an in silico analysis was conducted to predict their functional impact (e.g. their effect on miRNA-binding sites). Alleles in cis with the expanded (CAG)(n) were inferred from family data, and haplotypes were built. The effect of the alternative alleles on the AO and on SARA and NESSCA ataxia scales was tested. Nine variants, all previously described, were found. For eight variants, in silico analyses predicted (a) deleterious effects (rs10151135; rs55966267); (b) changes on miRNA-binding sites (rs11628764; rs55966267; rs709930) and (c) alterations of RNA-binding protein (RBP)-binding sites (rs1055996; rs910369; rs709930; rs10151135; rs3092822; rs7158733). Patients harbouring the alternative allele at rs10151135 had significantly higher SARA Axial subscores (p = 0.023), comparatively with those homozygous for the reference allele. Ten different haplotypes were obtained, one of which was exclusively found in cis with the expanded and four with the normal allele. These findings, which are relevant for the design of allele-specific therapies, warrant further investigation in independent MJD cohorts.