RNA gain-of-function mechanisms in short tandem repeat diseases

RNA gain-of-function pathomechanism in DM1. Bidirectional transcription of DM1 DMPK produces sense CUG^exp RNAs that bind MBNL proteins (red ovals), which undergo RNA–RNA, RNA–protein, and protein–protein multivalent interactions to form RNA foci or condensates (1). In contrast to sense transcription, antisense transcription yields very low-abundance RNAs with/without CAG^exp repeats (Gudde et al. 2017). MBNL sequestration in these foci together with phosphorylated CELF (blue sphere with black P) overexpression promotes fetal splicing patterns for target RNAs in adult tissues, and in DM1 skeletal muscle, exon 7A inclusion in CLCN1 mRNA (fetal isoform) (2) results in nonsense-mediated decay (NMD), CLCN1 loss, and myotonia (3). Somatic CTG expansions result in extremely long CUG^exp tracts that deplete MBNL (4) from the dilute nucleoplasmic pool, leading to release of intact or fragmented mutant DMPK mRNAs into the cytoplasm where they undergo RAN translation, giving rise to toxic RAN proteins (green and brown/yellow beads) (5). Mutant DMPK antisense transcripts may be exported into the cytoplasm at a low level, resulting in RAN translation of polyGln (Zu et al. 2011), and possibly polySer and polyAla, proteins.