{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T06:29:04Z","timestamp":1769927344875,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,29]]},"group-title":"Genetic and Genomic Medicine","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Although the CAG repeat expansion in the\n                  <jats:italic>ATXN3<\/jats:italic>\n                  gene was identified over 30 years ago as the cause of Machado-Joseph disease (MJD), the disorder remains untreatable. Notably, MJD is the most prevalent hereditary spinocerebellar ataxia worldwide and is particularly frequent in the Azores Islands (Portugal). This results from two independent founder effects, with two major ancestral lineages \u2013 \u201cJoseph\u201d and \u201cMachado\u201d - segregating in Azorean families. Although MJD pathogenesis is mainly driven by the (CAG)\n                  <jats:sub>n<\/jats:sub>\n                  expansion, regulatory\n                  <jats:italic>cis-<\/jats:italic>\n                  elements may modulate\n                  <jats:italic>ATXN3<\/jats:italic>\n                  expression, thereby influencing phenotypic variation. Here, we investigated allele-specific expression (ASE) of the\n                  <jats:italic>ATXN3<\/jats:italic>\n                  gene and examined whether distinct\n                  <jats:italic>ATXN3<\/jats:italic>\n                  lineages modulate the differential expression of non-expanded and expanded alleles, as well as its association with age at onset. We quantified\n                  <jats:italic>ATXN3<\/jats:italic>\n                  ASE in 38 cDNA samples from the blood of Azorean MJD expansion carriers. Notably, all 28 carriers of the Joseph lineage demonstrated higher relative expression of the expanded allele, whereas eight of the 10 Machado lineage carriers exhibited the opposite trend (Mann-Whitney U test,\n                  <jats:italic>p<\/jats:italic>\n                  &lt; 0.0001). By incorporating genetic and clinical data from an additional 76 Azorean MJD patients we found that, based on the expanded allele size alone, Joseph carriers would be expected to develop symptoms later than Machado carriers. Both lineages, however, report similar ages at onset. suggesting a counterbalance effect of\n                  <jats:italic>ATXN3<\/jats:italic>\n                  ASE: higher expression of the expanded allele in Joseph carriers may shift individuals toward earlier onset, while higher expression of the non-expanded allele in Machado carriers, may contribute to delayed onset. Our findings show that\n                  <jats:italic>ATXN3<\/jats:italic>\n                  exhibits haplotype-dependent allelic imbalance. This imbalance may be tissue-specific, underscoring the need for future studies using brain samples. Furthermore, it will be important to determine whether the observed association with age at onset is driven primarily by increased levels of the expanded protein, leading to enhanced protein toxicity, or by toxic effects at the RNA level.\n                <\/jats:p>","DOI":"10.64898\/2026.01.26.26344891","type":"posted-content","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:15:17Z","timestamp":1769732117000},"source":"Crossref","is-referenced-by-count":0,"title":["Allele-specific expression of\n                  <i>ATXN3<\/i>\n                  in blood samples of Machado-Joseph disease expansion carriers"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1759-762X","authenticated-orcid":false,"given":"Ana Rosa Vieira","family":"Melo","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade dos A\u00e7ores (UAc), Ponta Delgada, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal"}]},{"given":"Sandra","family":"Martins","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal"}]},{"given":"Sara","family":"Pav\u00e3o","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade dos A\u00e7ores (UAc), Ponta Delgada, Portugal"}]},{"given":"Lu\u00eds","family":"Teves","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade dos A\u00e7ores (UAc), Ponta Delgada, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal"},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto, Portugal"}]},{"given":"Ana F.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade dos A\u00e7ores (UAc), Ponta Delgada, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6306-1079","authenticated-orcid":false,"given":"Ahmed M.","family":"Sidky","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK"},{"name":"Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany"},{"name":"Biochemistry Division, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9846-1037","authenticated-orcid":false,"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto, Portugal"},{"name":"CGPP, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-8264","authenticated-orcid":false,"given":"Darren G.","family":"Monckton","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-3273","authenticated-orcid":false,"given":"Manuela","family":"Lima","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia, Universidade dos A\u00e7ores (UAc), Ponta Delgada, Portugal"},{"name":"Unidade Multidisciplinar de Investiga\u00e7\u00e3o Biom\u00e9dica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-0352","authenticated-orcid":false,"given":"Mafalda","family":"Raposo","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto, Portugal"},{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, 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