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

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Sandra Martins (Author) Other; Paula Coutinho (Author) Other; Isabel Silveira (Author) Other; Paola Giunti (Author) Other; Laura B Jardim (Author) Other; Francesc Calafell (Author) Other; Jorge Sequeiros (Author) ICBAS; Antonio Amorim (Author) FCUP

Journal

Title: American Journal of Medical Genetics, Part B, Neuropsychiatric Genetics

Vol. 147B

Pages: 439-446

ISSN: 1552-4841

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 18 Citations

Scopus - 18 Citations

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

Other information

Authenticus ID: P-003-YJY

DOI: 10.1002/ajmg.b.30624

Abstract (EN): 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 Ranking 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. (c) 2007 Wiley-Liss, Inc.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8