Pathogenic mechanisms of myotonic dystrophy

Abstract

DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3'-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)(n) or (CCUG)(n). The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.

Figure 1. Expanded CUG repeats in DM1 result in MBNL1 loss-of-function and CUGBP1 gain-of-function

MBNL1 is sequestered to the double-stranded hairpin structure formed by CUG repeats, depleting it from the nucleoplasm. The CUG repeats stimulate PKC activation through an unknown mechanism, which induces CUGBP1 hyperphosphorylation and stabilization. The downstream effects include disruption of alternative splicing, mRNA translation and mRNA decay.

Figure 2. The levels of MBNL1 and CUGBP1 in the nucleus control a subset of developmentally regulated splicing events that are reversed in DM1

In the embryonic stage, MBNL1 nuclear levels are low and CUGBP1 levels are high. During development, MBNL1 nuclear levels increase while CUGBP1 levels decrease, inducing an embryonic-to-adult transition of downstream splice targets (including IR exon 11, ClC-1 exons containing stop codons and cTNT exon 5). In DM1, MBNL1 is sequestered to CUG repeats, resulting in a decrease of functional MBNL1, while CUGBP1 levels are increased due to phosphorylation and stabilization. This simulates the embryonic condition and enhances expression of embryonic isoforms in adults, resulting in multiple disease symptoms.