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Juvenile CLN3 disease is the most prevalent type, and the most common pathogenic variant shared by most patients is the \u201c1-kb\u201d deletion which removes two internal coding exons (7 and 8) in <jats:italic>CLN3<\/jats:italic>. Previously, we identified two transcripts in patient fibroblasts homozygous for the 1-kb deletion: the \u2018major\u2019 and \u2018minor\u2019 transcripts. To understand the full variety of disease transcripts and their role in disease pathogenesis, it is necessary to first investigate <jats:italic>CLN3<\/jats:italic> transcription in \u201chealthy\u201d samples without juvenile CLN3 disease.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We leveraged PacBio long-read RNA sequencing datasets from ENCODE to investigate the full range of <jats:italic>CLN3<\/jats:italic> transcripts across various tissues and cell types in human control samples. Then we sought to validate their existence using data from different sources.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found that a readthrough gene affects the quantification and annotation of <jats:italic>CLN3.<\/jats:italic> After taking this into account, we detected over 100 novel <jats:italic>CLN3<\/jats:italic> transcripts, with no dominantly expressed <jats:italic>CLN3<\/jats:italic> transcript. The most abundant transcript has median usage of 42.9%. Surprisingly, the known disease-associated \u2018major\u2019 transcripts are detected. Together, they have median usage of 1.5% across 22 samples. Furthermore, we identified 48 <jats:italic>CLN3<\/jats:italic> ORFs, of which 26 are novel. The predominant ORF that encodes the canonical CLN3 protein isoform has median usage of 66.7%, meaning around one-third of <jats:italic>CLN3<\/jats:italic> transcripts encode protein isoforms with different stretches of amino acids. The same ORFs could be found with alternative UTRs. Moreover, we were able to validate the translational potential of certain transcripts using public mass spectrometry data.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Overall, these findings provide valuable insights into the complexity of <jats:italic>CLN3<\/jats:italic> transcription, highlighting the importance of studying both canonical and non-canonical CLN3 protein isoforms as well as the regulatory role of UTRs to fully comprehend the regulation and function(s) of <jats:italic>CLN3<\/jats:italic>. This knowledge is essential for investigating the impact of the 1-kb deletion and rare pathogenic variants on <jats:italic>CLN3<\/jats:italic> transcription and disease pathogenesis.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12920-024-02017-z","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T09:01:57Z","timestamp":1728032517000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CLN3 transcript complexity revealed by long-read RNA sequencing analysis"],"prefix":"10.1186","volume":"17","author":[{"given":"Hao-Yu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Minnis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Gustavsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Ryten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara E.","family":"Mole","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,10,4]]},"reference":[{"issue":"2","key":"2017_CR1","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1212\/WNL.0b013e31825f0547","volume":"79","author":"RE Williams","year":"2012","unstructured":"Williams RE, Mole SE. 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