Science · 1998 · 818 citations · 17 references
Life SciencesGeneticsMolecular BiologyGene ExpressionRna ProcessingTranscriptional RegulationAlternative SplicingMuscular DystrophyRna SplicingRna-protein InteractionsTranslation RegulationTranslational RegulationAlternative Splicing RegulationCardiac TroponinsDisease-associated Splicing DefectsGain-of-function ModelsMuscular Dystrophy PathophysiologyPre-messenger Rna 3' End ProcessingPre-messenger Rna SplicingRna Splicing Defects
Myotonic dystrophy is caused by a CTG expansion in the 3′ UTR of the DM gene, and expanded allele RNAs are thought to exert a gain‑of‑function effect by aberrantly binding proteins to CUG repeats. The study shows that the CUG‑binding protein CUG‑BP binds cardiac troponin T pre‑mRNA, alters its alternative splicing, and that this splicing defect occurs in DM muscle and in cells expressing CUG repeats, suggesting that CUG‑BP‑mediated post‑transcriptional dysregulation contributes to disease.
Myotonic dystrophy (DM) is caused by a CTG expansion in the 3′ untranslated region of the DM gene. One model of DM pathogenesis suggests that RNAs from the expanded allele create a gain-of-function mutation by the inappropriate binding of proteins to the CUG repeats. Data presented here indicate that the conserved heterogeneous nuclear ribonucleoprotein, CUG-binding protein (CUG-BP), may mediate the trans-dominant effect of the RNA. CUG-BP was found to bind to the human cardiac troponin T (cTNT) pre–messenger RNA and regulate its alternative splicing. Splicing of cTNT was disrupted in DM striated muscle and in normal cells expressing transcripts that contain CUG repeats. Altered expression of genes regulated posttranscriptionally by CUG-BP therefore may contribute to DM pathogenesis.
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