title: 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.
authors.affiliation: IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal. smartins@ipatimup.pt
authors.forename: Sandra
authors.initials: S
authors.lastname: Martins
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.forename: Isabel
authors.initials: I
authors.lastname: Silveira
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.forename: Laura B
authors.initials: LB
authors.lastname: Jardim
authors.forename: Francesc
authors.initials: F
authors.lastname: Calafell
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.forename: António
authors.initials: A
authors.lastname: Amorim
mesh_terms: D000367:Age Factors; D000067699:Ataxin-3; D042822:Genomic Instability; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns; D017827:Machado-Joseph Disease / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010290:Parents; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D012737:Sex Factors; D018911:Trinucleotide Repeats
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3