{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T11:55:34Z","timestamp":1769946934002,"version":"3.49.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2007,10,19]],"date-time":"2007-10-19T00:00:00Z","timestamp":1192752000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt B"],"published-print":{"date-parts":[[2008,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In repeat expansion disorders, the size of pathological alleles is the most relevant factor accounting for the disease severity and age\u2010at\u2010onset, emphasizing the clinical significance of their underlying intergenerational instability. In one of these diseases, Machado\u2013Joseph disease (MJD), the sex of transmitting progenitor and the <jats:styled-content>C<\/jats:styled-content><jats:sup>987<\/jats:sup>GG\/<jats:styled-content>G<\/jats:styled-content><jats:sup>987<\/jats:sup>GG polymorphism are the best studied factors acting on intergenerational instability of expanded alleles. Here, we assessed the influence of other <jats:italic>cis<\/jats:italic> and inter\u2010allelic acting factors, at the <jats:italic>ATXN3<\/jats:italic> locus, through the analysis of MJD lineages, flanking STR\u2010based 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\u2010based 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 <jats:italic>cis<\/jats:italic> elements acting up\u2010 or downstream the <jats:italic>ATXN3<\/jats:italic> locus. Considering the increased amplitude of expansions seen in older transmitting fathers, a repair\u2010based mechanism may be suggested for the meiotic instability at this <jats:italic>locus<\/jats:italic>; furthermore, the lack of correlation between the initial repeat size and degree of instability did not support a replication\u2010based 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. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.b.30624","type":"journal-article","created":{"date-parts":[[2007,10,19]],"date-time":"2007-10-19T17:15:50Z","timestamp":1192814150000},"page":"439-446","source":"Crossref","is-referenced-by-count":25,"title":["<i>Cis<\/i>\u2010acting factors promoting the CAG intergenerational instability in Machado\u2013Joseph disease"],"prefix":"10.1002","volume":"147B","author":[{"given":"Sandra","family":"Martins","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Coutinho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Silveira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Giunti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura B.","family":"Jardim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesc","family":"Calafell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ant\u00f3nio","family":"Amorim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,5,20]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"414","article-title":"Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy","volume":"54","author":"Ashizawa T","year":"1994","journal-title":"Am J Hum Genet"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.6.1061"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.30125"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng870"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-006-0164-7"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.3.439"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320450330"},{"key":"e_1_2_6_9_1","doi-asserted-by":"crossref","unstructured":"IgarashiS TakiyamaY CancelG RogaevaEA SasakiH WakisakaA ZhouYX TakanoH EndoK SanpeiK OyakeM TanakaH StevaninG AbbasN D\u00fcrrA RogaevEI SherringtonR TsudaT IkedaM CassaE NishizawaM BenomarA JulienJ WeissenbachJ WangGX AgidY St George\u2010HyslopPH BriceA TsujiS.1996.Intergenerational instability of the CAG repeat of the gene for Machado\u2010Joseph disease (MJD1) is affected by the genotype of the normal chromosome: Implications for the molecular mechanisms of the instability of the CAG repeat. 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