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

Full 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.(c) 2007 Wiley-Liss, Inc.

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Author information

Author/s: Martins, Sandra (S); Coutinho, Paula (P); Silveira, Isabel (I); Giunti, Paola (P); Jardim, Laura B (LB); Calafell, Francesc (F); Sequeiros, Jorge (J); Amorim, António (A);

Affiliation: IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal. smartins(-atsign-)ipatimup.pt

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (Am J Med Genet B Neuropsychiatr Genet), published in United States. (Language: eng)

Reference: 2008-Jun; vol 147B (issue 4) : pp 439-46

Dates: Created 2008/05/26; Completed 2008/07/23;

PMID: 17948873, status: MEDLINE (last retrieval date: 11/6/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Nerve Tissue Proteins - genetics
Nuclear Proteins - genetics
Parents
Pedigree
Repressor Proteins - genetics
Sex Factors
Trinucleotide Repeats

Associated Chemicals: Nerve Tissue Proteins (0) ; Nuclear Proteins (0) ; Repressor Proteins (0) ; ATXN3 protein, human (EC 3.4.22.-)

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