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A major pathogenic event in DM1 is the sequestration of muscleblind-like (MBNL) proteins by CUG repeat-containing RNAs transcribed from expanded repeats. Among the various symptoms of DM1, lipid abnormalities and liver dysfunction are frequent but remain understudied. Although abnormal splicing of insulin receptor RNA is implicated, it cannot fully explain these abnormalities. To investigate the molecular mechanisms, we performed transcriptome analysis of postmortem livers from patients with DM1 and Mbnl-knockout mice. RNA-sequencing revealed differentially expressed genes (DEGs) and aberrant splicing in DM1 livers. A comparison of Mbnl1- and Mbnl2-knockout mouse livers indicated that MBNL1 accounts for some of the transcriptomic changes observed in patients with DM1. The DEGs included those related to lipid metabolism and liver fibrosis. DM1-associated changes in the liver transcriptome partially resolved sexual dimorphism in gene expression and uncovered distinct sex-specific pathway alterations. Besides the known MBNL-regulated genes, those related to lipid and glucose metabolism were identified in the aberrant splicing clusters detected in DM1. A correlation between serum gamma-glutamyl transferase levels and overall splicing abnormalities was observed, linking splicing changes in the liver to clinical abnormalities. These findings provide new insights into the molecular basis of DM1-related metabolic and hepatic abnormalities, enhancing our understanding of the systemic effects of this disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf124","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:02:29Z","timestamp":1752501749000},"page":"1718-1732","source":"Crossref","is-referenced-by-count":2,"title":["Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1"],"prefix":"10.1093","volume":"34","author":[{"given":"Aono","family":"Fukumoto","sequence":"first","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, The University of Osaka , 1-7 Yamadaoka, Suita, Osaka, 565-0871 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,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Hama","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, The University of Osaka , 1-7 Yamadaoka, Suita, Osaka, 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Yasumizu","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Immunology Frontier Research Center, The University of Osaka , 3-1 Yamadaoka, Suita, Osaka, 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Shiotsu","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, The University of Osaka , 1-7 Yamadaoka, Suita, Osaka, 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Department of Neurology, NHO Osaka Toneyama Medical Center , 5-1-1 Toneyama, Toyonaka, Osaka 560-8552 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis A","family":"Nutter","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine , 2033 Mowry Rd., Gainesville, FL 32610 ,","place":["United States"]},{"name":"Department of Biochemistry, University of Missouri School of Medicine , 1030 Hitt St., Columbia, MO 65211 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Kubota","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, The University of Osaka , 1-7 Yamadaoka, Suita, Osaka, 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harutoshi","family":"Fujimura","sequence":"additional","affiliation":[{"name":"Department of Neurology, NHO Osaka Toneyama Medical Center , 5-1-1 Toneyama, Toyonaka, Osaka 560-8552 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kino","sequence":"additional","affiliation":[{"name":"Department of RNA Pathobiology and Therapeutics, Meiji Pharmaceutical University , 2-522-1, Noshio, Kiyose, Tokyo 204-8588 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6245-5367","authenticated-orcid":false,"given":"Maurice S","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine , 2033 Mowry Rd., Gainesville, FL 32610 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimiko","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Neurology, NHO Osaka Toneyama Medical Center , 5-1-1 Toneyama, Toyonaka, Osaka 560-8552 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5513-5012","authenticated-orcid":false,"given":"Masanori P","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, The University of Osaka , 1-7 Yamadaoka, Suita, Osaka, 565-0871 ,","place":["Japan"]},{"name":"United Graduate School of Child Development (UGSCD), The University of Osaka , 2-2 Yamadaoka, Suita, Osaka, 565-0871 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