CTG repeat expansion disrupts RNA splicing and WNT/BMP–HOX transcriptional programs in patient-derived models of myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansion in the DMPK gene, resulting in the formation of nuclear CUG RNA foci, sequestration of MBNL1, and widespread defects in RNA processing. Here, we investigated the molecular consequences of CTG expansion using a multi-stage patient-derived platform comprising fibroblasts, induced pluripotent stem cells (iPSCs), and iPSC-derived cardiomyocytes (CMs). DM1 fibroblasts exhibited repeat length-associated MBNL1 sequestration and splicing abnormalities in INSR , ZASP , and MBNL1 . Transcriptome analysis further revealed extensive dysregulation of developmental gene networks, particularly within HOX clusters, together with altered expression of WNT/BMP signaling components. Despite harboring expanded repeats, DM1 fibroblasts were successfully reprogrammed into integration-free iPSCs that retained pluripotency and tri-lineage differentiation potential. DM1-iPSC-derived CMs displayed CUG RNA foci, MBNL1 sequestration, heterogeneous RBM20 localization, multiple DM1-relevant splicing abnormalities, more heterogeneous sarcomeric marker organization, and impaired calcium handling. Collectively, these findings support the use of DM1-iPSC-derived CMs as a disease-relevant model for investigating DM1-associated RNA-processing and cardiac phenotypes.

The authors' abstract, as published at the source. Stem Cell Research & Therapy, 2026 · DOI ↗