Muscleblind-like protein 1 (MBNL1)–CUG RNA complex (MBNL1–CUG RNA complex)

The Muscleblind-like protein 1 (MBNL1)–CUG RNA complex is a pathological ribonucleoprotein assembly that serves as the primary driver of Myotonic Dystrophy type 1 (DM1) pathogenesis (Miller et al., 2000). In DM1, an expansion of CTG repeats in the 3' untranslated region of the DMPK gene results in the transcription of toxic RNA containing long CUG repeats, which fold into stable hairpin structures (NIH, 2023). These hairpins have a high affinity for MBNL1, a master regulator of alternative splicing, sequestering it into insoluble nuclear foci and preventing it from performing its normal cellular functions (UniProt Q9NR56). This functional loss of MBNL1 leads to widespread "spliceopathy," where fetal isoforms of proteins are inappropriately expressed in adult tissues, causing symptoms like myotonia, muscle wasting, and cardiac conduction defects (Nakamori et al., 2013). Therapeutic interventions focus on small molecules or antisense oligonucleotides that can disrupt this complex, thereby liberating MBNL1 to restore normal splicing patterns. Research has identified several small molecules, such as pentamidine and erythromycin, that can competitively bind the CUG repeats or the protein to break the complex (Warfman et al., 2009; Nakamori et al., 2016).

Other names

MBNL1–(CUG)n complexMuscleblind-like 1–expanded CUG repeat complexMBNL1–r(CUG)exp complexMBNL1–DMPK RNA complex

Small molecule-mediated disruption of the MBNL1–CUG RNA complex to reverse protein sequestration and restore physiological RNA splicing.