Muscleblind-like protein 1 interaction with expanded CUG repeat RNA (MBNL1-CUGexp RNA)

The functional interaction between Muscleblind-like protein 1 (MBNL1) and expanded CUG repeat RNA (CUGexp-DMPK) is the primary pathogenic driver of Myotonic Dystrophy Type 1 (DM1) (Miller et al., 2000). In DM1, an unstable CTG expansion in the 3' UTR of the DMPK gene is transcribed into toxic RNA containing long CUG repeats, which fold into stable hairpin structures that sequester MBNL1 into nuclear foci (Lin et al., 2006). This sequestration leads to a loss of MBNL1 function, resulting in the mis-splicing of numerous downstream pre-mRNAs critical for muscle and cardiac function, such as CLCN1 and INSR (Kanadia et al., 2003; Savkur et al., 2001). Therapeutic interventions focus on liberating MBNL1 by either degrading the mutant DMPK transcript or using small molecules to block the binding interface between the protein and the RNA repeats (Wheeler et al., 2012). Restoring MBNL1 activity is expected to reverse the spliceopathy and alleviate the clinical symptoms of myotonia and muscle wasting (Nakamori et al., 2013). Current clinical candidates include antibody-oligonucleotide conjugates and antisense oligonucleotides designed to reduce the toxic RNA burden (Avidity Biosciences, 2024; Dyne Therapeutics, 2024).

Other names

MBNL1-CUGexp complexMBNL1 sequestration by CUGexp RNADMPK CUG expansion-MBNL1 interactionDM1 RNA-protein interaction

Therapeutic strategies aim to disrupt the interaction between MBNL1 and expanded CUG repeats, either by degrading the toxic CUGexp-DMPK RNA using antisense oligonucleotides (ASOs) or siRNA, or by using small molecules to displace MBNL1 from the RNA foci, thereby restoring MBNL1's normal function in regulating alternative splicing (Wheeler et al., 2012; Avidity Biosciences, 2024).