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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2008

Autores

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

Revista

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

Vol. 147B

Páginas: 439-446

ISSN: 1552-4841

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 18 Citações

Scopus - 18 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina clínica

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 8