Cis‐acting factors promoting the CAG intergenerational instability in Machado–Joseph disease

Abstract

In repeat expansion disorders, the size of pathological alleles is the most relevant factor accounting for the disease severity and age-at-onset, emphasizing the clinical significance of their underlying intergenerational instability. In one of these diseases, Machado-Joseph disease (MJD), the sex of transmitting progenitor and the C(987)GG/G(987)GG polymorphism are the best studied factors acting on intergenerational instability of expanded alleles. Here, we assessed the influence of other cis and inter-allelic acting factors, at the ATXN3 locus, through the analysis of MJD lineages, flanking STR-based haplotypes, the initial repeat size and parental age. A total of 100 transmissions of the expanded MJD allele were analyzed according to the sex of the transmitting parent. We have shown that independent origin mutations (identified by intragenic SNP-based haplotypes) behave differently, as the status of instability (contraction, no change or further expansion) is concerned. Indeed, 72% of expansions were associated to the worldwide spread TTACAC lineage, whereas the GTGGCA displayed 75% of all contractions observed. The analysis of flanking recombinant haplotypes did not suggest any further distant cis elements acting up- or downstream the ATXN3 locus. Considering the increased amplitude of expansions seen in older transmitting fathers, a repair-based mechanism may be suggested for the meiotic instability at this locus; furthermore, the lack of correlation between the initial repeat size and degree of instability did not support a replication-based mechanism. In summary, our findings point to different mechanisms of instability underlying male and female meioses, as well as contraction and expansion processes in MJD.