学術雑誌論文

学術雑誌論文

text

Human Molecular Genetics. 2025, 34(20), p. 1718-1732

Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1

Oxford University Press

英語

text

2025-08-13

https://doi.org/10.1093/hmg/ddaf124

This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Fukumoto A., Yamanaka T., Yanaizu M., et al., Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1, Human Molecular Genetics 34(20), 1718 (2025), https://doi.org/10.1093/hmg/ddaf124 is available online at: https://doi.org/10.1093/hmg/ddaf124.

Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK 3′-untranslated region, affecting multiple organs, including the skeletal muscles, eyes, heart, central nervous system, and endocrine system. 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.

The full-text file will be made open to the public on 13 August 2026 in accordance with the publisher's policy.

103068

Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1

Oxford University Press

英語

2025-08-13

Human Molecular Genetics

34

20

1718

1732

https://doi.org/10.1093/hmg/ddaf124

https://hdl.handle.net/11094/103068