Muscleblind-like protein 1 (MBNL1)–CUG expansion RNA interaction (MBNL1–CUGexp interaction)

Muscleblind-like protein 1 (MBNL1) is a critical RNA-binding protein responsible for regulating alternative splicing, mRNA localization, and stability during development (UniProt Q9NR56). In Myotonic Dystrophy Type 1 (DM1), an expansion of CUG repeats in the 3' untranslated region of the Myotonin-protein kinase (DMPK) gene creates toxic RNA hairpins that sequester MBNL1 into insoluble nuclear foci (Miller et al., 2000). This sequestration leads to a functional depletion of MBNL1, resulting in the mis-splicing of numerous downstream effector genes such as Chloride voltage-gated channel 1 (CLCN1) and Insulin receptor (INSR), which drives the clinical symptoms of myotonia and insulin resistance (Kanadia et al., 2003). Therapeutic strategies targeting this interaction focus on disrupting the MBNL1–CUGexp complex to liberate the protein and restore its regulatory activity. Small molecules like pentamidine have been shown to displace MBNL1 from these repeats, while antisense oligonucleotides and siRNA-based therapies, such as Delpacibart zotirsen (AOC-1001) and Delpacibart etedesiran (DYNE-101), aim to degrade the expanded RNA transcripts (Warf et al., 2009; Avidity Biosciences, 2024). Successfully targeting this interaction represents a primary goal in DM1 drug development to reverse the underlying "spliceopathy" of the disease.

Other names

MBNL1-CUG repeat interactionMBNL1 sequestration by CUGexp RNAMuscleblind-like 1-RNA foci interactionDMPK CUG expansion-MBNL1 complex

Disruption of the MBNL1–CUGexp RNA complex to release sequestered MBNL1 protein, or degradation of the CUG-expanded DMPK mRNA to prevent sequestration, thereby restoring normal alternative splicing of MBNL1 target transcripts.