{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:11:41Z","timestamp":1775977901177,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,9,12]],"date-time":"2018-09-12T00:00:00Z","timestamp":1536710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006310","name":"Medicinska Forskningsr\u00e5det","doi-asserted-by":"publisher","award":["K2012\u201068X\u201015022\u201009\u20103"],"award-info":[{"award-number":["K2012\u201068X\u201015022\u201009\u20103"]}],"id":[{"id":"10.13039\/501100006310","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004885","name":"Ume\u00e5 Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004885","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen & Gen Med"],"published-print":{"date-parts":[[2018,11]]},"abstract":"Abstract<\/jats:title>Background<\/jats:title>Hereditary myopathy with lactic acidosis (HML<\/jats:styled-content>) is an autosomal recessive disease caused by an intron mutation in the iron\u2010sulfur cluster assembly (ISCU<\/jats:styled-content><\/jats:italic>) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA<\/jats:styled-content> transcript, giving rise to a truncated nonfunctional ISCU<\/jats:styled-content> protein. Using an ISCU<\/jats:styled-content><\/jats:italic> mini\u2010gene system, we have previously shown that PTBP<\/jats:styled-content>1 can act as a repressor of the mis\u2010splicing of ISCU<\/jats:styled-content><\/jats:italic>, where overexpression of PTBP<\/jats:styled-content>1 resulted in a decrease of the incorrect splicing. In this study, we wanted to, in more detail, analyze the role of PTBP<\/jats:styled-content>1 in the regulation of endogenous ISCU<\/jats:styled-content><\/jats:italic> mis\u2010splicing.<\/jats:p><\/jats:sec>Methods<\/jats:title>Overexpression and knockdown of PTBP<\/jats:styled-content>1 was performed in myoblasts from two HML<\/jats:styled-content> patients and a healthy control. Quantification of ISCU<\/jats:styled-content><\/jats:italic> mis\u2010splicing was done by qRTPCR<\/jats:styled-content>. Biotinylated ISCU<\/jats:styled-content><\/jats:italic> RNA<\/jats:styled-content>, representing wildtype and mutant intron sequence, was used in a pull\u2010down assay with nuclear extracts from myoblasts. Levels of PTBP<\/jats:styled-content>1 in human cell lines and mice tissues were analyzed by qRTPCR<\/jats:styled-content> and western blot.<\/jats:p><\/jats:sec>Results<\/jats:title>PTBP<\/jats:styled-content>1 overexpression in HML<\/jats:styled-content> patient myoblasts resulted in a substantial decrease of ISCU<\/jats:styled-content><\/jats:italic> mis\u2010splicing while knockdown of PTBP<\/jats:styled-content>1 resulted in a drastic increase. The effect could be observed in both patient and control myoblasts. We could also show that PTBP<\/jats:styled-content>1 interacts with both the mutant and wild\u2010type ISCU<\/jats:styled-content><\/jats:italic> intron sequence, but with a higher affinity to the mutant sequence. Furthermore, low levels of PTBP<\/jats:styled-content>1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU<\/jats:styled-content><\/jats:italic>.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Our results show that PTBP<\/jats:styled-content>1 acts as a dominant repressor of ISCU<\/jats:styled-content><\/jats:italic> mis\u2010splicing. We also show an inverse correlation between the levels of PTBP<\/jats:styled-content>1 and ISCU<\/jats:styled-content><\/jats:italic> mis\u2010splicing, suggesting that the high level of mis\u2010splicing in the skeletal muscle is primarily due to the low levels of PTBP<\/jats:styled-content>1.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.413","type":"journal-article","created":{"date-parts":[[2018,9,13]],"date-time":"2018-09-13T04:10:20Z","timestamp":1536811820000},"page":"887-897","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["PTBP<\/scp>1 acts as a dominant repressor of the aberrant tissue\u2010specific splicing of ISCU<\/scp><\/i> in hereditary myopathy with lactic acidosis"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6632-5770","authenticated-orcid":false,"given":"Denise F. 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