{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T02:52:10Z","timestamp":1793069530159,"version":"4.5.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Ulm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The disease-causing mutation in Huntington disease (HD) is a CAG trinucleotide expansion in the huntingtin (\n                      <jats:italic>HTT<\/jats:italic>\n                      ) gene. The mutated CAG tract results in the production of a small RNA,\n                      <jats:italic>HTT1a<\/jats:italic>\n                      , coding for only exon 1 of HTT.\n                      <jats:italic>HTT1a<\/jats:italic>\n                      is generated by a block in the splicing reaction of\n                      <jats:italic>HTT<\/jats:italic>\n                      exon 1 to exon 2 followed by cleavage in intron 1 and polyadenylation. Translation of\n                      <jats:italic>HTT1a<\/jats:italic>\n                      leads to the expression of the highly toxic HTT exon 1 protein fragment. We have previously shown that the levels of\n                      <jats:italic>HTT1a<\/jats:italic>\n                      expression in mouse models of HD is dependent on the CAG repeat length. However, these data are lacking for human tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To answer this question, we developed highly sensitive digital PCR assays to determine\n                      <jats:italic>HTT1a<\/jats:italic>\n                      levels in human samples. These assays allow the absolute quantification of transcript numbers and thus also facilitate the comparison of\n                      <jats:italic>HTT1a<\/jats:italic>\n                      levels between tissues, cell types and across different studies. Furthermore, we measured CAG repeat sizes for every sample used in the study. Finally, we analysed our data with ANOVA and linear modelling to determine the correlation of\n                      <jats:italic>HTT1a<\/jats:italic>\n                      expression levels with CAG repeat sizes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In summary, we show that\n                      <jats:italic>HTT1a<\/jats:italic>\n                      is indeed expressed in a CAG  repeat-length-dependent manner in human\n                      <jats:italic>post mortem<\/jats:italic>\n                      brain tissues as well as in several peripheral cell types. In particular, PBMCs show a statistically significant positive correlation of\n                      <jats:italic>HTT1a<\/jats:italic>\n                      expression with CAG repeat length, and elevated\n                      <jats:italic>HTT1a<\/jats:italic>\n                      expression levels even in the adult-onset CAG repeat range.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results show that\n                      <jats:italic>HTT1a<\/jats:italic>\n                      expression occurs throughout a wide range of tissues and likely with all CAG lengths. Our data from peripheral sample sources demonstrate that HTT1a is indeed generated throughout the body in a CAG repeat-length-dependent manner. Therefore, the levels of\n                      <jats:italic>HTT1a<\/jats:italic>\n                      might be a sensitive marker of disease state and\/or progression and should be monitored over time, especially in clinical trials targeting HTT expression.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-024-00801-2","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T09:01:43Z","timestamp":1709888503000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Huntingtin HTT1a is generated in a CAG repeat-length-dependent manner in human tissues"],"prefix":"10.1186","volume":"30","author":[{"given":"Franziska","family":"Hoschek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Natan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirupa","family":"Sathasivam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alshaimaa","family":"Abdelmoez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"von Einem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian P.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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All experimental methods comply with the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors agree to the publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"B.v.E. has been a full-time employee of NatIgGs GmbH since January 2023. All other authors declare no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"36"}}