Document Detail

Cis-acting factors promoting the CAG intergenerational instability in Machado-Joseph disease.
MedLine Citation:
PMID:  17948873     Owner:  NLM     Status:  MEDLINE    
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.
Sandra Martins; Paula Coutinho; Isabel Silveira; Paola Giunti; Laura B Jardim; Francesc Calafell; Jorge Sequeiros; António Amorim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics     Volume:  147B     ISSN:  1552-485X     ISO Abbreviation:  Am. J. Med. Genet. B Neuropsychiatr. Genet.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-05-26     Completed Date:  2008-07-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101235742     Medline TA:  Am J Med Genet B Neuropsychiatr Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  439-46     Citation Subset:  IM    
Copyright Information:
(c) 2007 Wiley-Liss, Inc.
IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal.
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MeSH Terms
Age Factors
Genomic Instability
Inheritance Patterns
Machado-Joseph Disease / genetics*
Nerve Tissue Proteins / genetics*
Nuclear Proteins / genetics*
Repressor Proteins / genetics*
Sex Factors
Trinucleotide Repeats*
Reg. No./Substance:
0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/Repressor Proteins; EC 3.4.22.-/ATXN3 protein, human

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