Transcript diversity of Machado-Joseph disease gene (ATXN3) is not directly determined by SNPs in exonic or flanking intronic regions.

Alternative splicing (AS) of pre-mRNA is an important regulatory mechanism that enables one gene to produce multiple mature transcripts and, therefore, multiple protein isoforms. Besides the information content of core splicing signals, additional cis-regulatory elements (splicing enhancers and silencers) are needed to precisely define exons. AS is well documented in ATXN3 gene, which encodes for ataxin-3 and, when mutated, is responsible for Machado-Joseph disease (MJD). By studying MJD patients and controls, we have previously identified 56 alternative transcript variants for this gene; some were predicted to encode "protective" ataxin-3 isoforms, making then pertinent to understand AS regulation. The present study aims to investigate the relationship between variation in ATXN3 cis-regulatory motifs and AS variants found for each individual. We have sequenced exonic and flanking intronic ATXN3 regions, in genomic DNA from MJD patients and controls previously studied. None of the 10 single nucleotide polymorphisms (SNPs) that were found was located in core splicing signals. In silico analysis showed those SNPs implied losses and gains of recognition motifs for splicing factors. Each particular allele was not directly reflected in alterations of the resulting splicing variants, indicating that AS cannot be determined solely by these cis-elements, but should result from a more complex mode of regulation.