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This process, called repeat-associated non-AUG (RAN) translation, generates aggregation-prone proteins, but its molecular basis remains unclear. Here, using affinity capture of CAG-repeat-containing RNAs, we identify a previously unannotated promoter ~33 kb upstream of the\n                  <jats:italic>HTT<\/jats:italic>\n                  gene. Transcripts initiating from this promoter undergo repeat-length-dependent aberrant splicing into exon 1 of the canonical\n                  <jats:italic>HTT<\/jats:italic>\n                  , embedding the CAG repeat in AUG-initiated frames encoding polyalanine and polyserine proteins. Comparative genomics indicates that this upstream promoter is primate-specific, helping explain inconsistencies across rodent models. Our findings establish a direct, AUG-dependent, splicing-mediated mechanism for out-of-frame repeat proteins in HD, expose critical gaps in current animal models, and identify novel splice junctions as potential therapeutic targets.\n                <\/jats:p>","DOI":"10.1101\/2025.10.20.683480","type":"posted-content","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T03:35:20Z","timestamp":1761017720000},"source":"Crossref","is-referenced-by-count":2,"title":["A distal promoter and aberrant splicing enable canonical translation of out-of-frame proteins in Huntington\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3450-3151","authenticated-orcid":false,"given":"Rachel","family":"Anderson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanishk","family":"Soni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankur","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102306101335000_2025.10.20.683480v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.03.011"},{"key":"2025102306101335000_2025.10.20.683480v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00382-6"},{"key":"2025102306101335000_2025.10.20.683480v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-63233-3.00009-9"},{"key":"2025102306101335000_2025.10.20.683480v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1013343108"},{"key":"2025102306101335000_2025.10.20.683480v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ng1827"},{"key":"2025102306101335000_2025.10.20.683480v1.6","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899023"},{"key":"2025102306101335000_2025.10.20.683480v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.10.038"},{"key":"2025102306101335000_2025.10.20.683480v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2021.11.001"},{"key":"2025102306101335000_2025.10.20.683480v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.01.006"},{"key":"2025102306101335000_2025.10.20.683480v1.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1919197117"},{"key":"2025102306101335000_2025.10.20.683480v1.11","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202401465R"},{"key":"2025102306101335000_2025.10.20.683480v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.01.006"},{"key":"2025102306101335000_2025.10.20.683480v1.13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2215071120"},{"key":"2025102306101335000_2025.10.20.683480v1.14","doi-asserted-by":"publisher","DOI":"10.4161\/rna.26706"},{"key":"2025102306101335000_2025.10.20.683480v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw187"},{"key":"2025102306101335000_2025.10.20.683480v1.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143563"},{"key":"2025102306101335000_2025.10.20.683480v1.17","first-page":"207","article-title":"Fundamentals of sequencing of difficult templates--an overview","volume":"17","year":"2006","journal-title":"J. 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