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Repeat expansion diseases: when a good RNA turns bad

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An increasing number of dominantly inherited diseases have now been linked with expansion of short repeats within specific genes. Although some of these expansions affect protein function or result in haploinsufficiency, a significant portion cause pathogenesis through production of toxic RNA molecules that alter cellular metabolism. In this review, we examine the criteria that influence toxicity of these mutant RNAs and discuss new developments in therapeutic approaches. Copyright © 2010 John Wiley & Sons, Ltd.

Figure 1.

Repeat expansions can occur in 5′UTRs, the coding region, introns or 3′UTRs. Normal and premutation alleles do not show disease symptoms, but premutation alleles are primed to expand in the next generation. As repeats get longer symptoms are seen at an earlier age and are more severe. Note that repeat lengths in introns and 3′UTRs can become much larger than in coding regions and 5′UTRs.

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Figure 2.

CUG‐repeat RNA accumulates in nuclear foci in type 1 myotonic dystrophy (DM1) patient fibroblasts. Fluorescence in situ hybridization (FISH) using a Cy3(CAG)8 oligonucleotide probe. Foci containing toxic RNA species appear red, whereas the nucleus stained with DAPI appears blue..

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Figure 3.

Toxic RNAs have myriad downstream effects on cellular metabolism. Expression of repeat‐containing RNAs can induce hypermethylation and heterochromatinization of the neighboring DNA (1). The double‐stranded hairpin structure formed by the repeat RNAs can sequester RNA‐binding proteins such as MBNL1 (2). This leads to altered splicing of MBNL1 target RNAs (3). In addition, in some cases kinase pathways are activated through unknown mechanisms, leading to aberrant phosphorylation and localization of CUGBP1 (4). This also has impact on splice site choice and perhaps on decay and translation of CUGBP1 target messenger RNAs (mRNAs) (5 and 6). The toxic RNA can be cleaved by the Dicer protein to generate siRNAs that may inhibit expression of genes containing complementary repeats (7). This siRNA pathway can also induce silencing of the toxic repeat‐containing gene (8). Finally, when CAG repeats lie within a coding region they can encode polyglutamine, which also has toxic effects on the cell (9).

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Figure 4.

Effects of various therapeutics on toxic RNA and cellular metabolism in DM1. (a) Wild‐type dystrophia myotonica protein kinase (DMPK) RNA does not interact with MBNL1 (red circles) and MBNL1 is distributed throughout the nucleus (blue). In wild‐type cells, MBNL1 and CUGBP1 (yellow circles) are directed to their target pre‐mRNA and appropriately regulate splice site selection. (b) In mutant cells, MBNL1 is titrated away from its normal targets by the repeat hairpin and accumulates in nuclear foci. CUGBP1 is hyperphosphorylated and overexpressed. This alters splice site selection. (c) Antisense oligonucleotides (AONs) or morpholinos (green lines) disrupt the hairpin RNA and/or the MBNL1 interaction, which releases MBNL1 to perform its usual roles. (d) Ribozymes (scissors) can degrade the hairpin RNA, releasing MBNL1 to correct splicing. (e) Small molecules to disrupt MBNL1 binding (green diamonds) release MBNL1 to perform its normal roles. (f) Increasing MBNL1 expression can flood the cell with excess MBNL1 allowing it to bind its splicing targets in addition to mutant DMPK mRNA. (g) AONs directed to splice sites prevent splicing at the incorrect site. (h) Kinase inhibitors reduce CUGBP1 phosphorylation and overexpression and favor normal splice site choice. The effects on CUGBP1 phosphorylation and abundance are not easily predicted in all cases as the mechanisms leading to hyperphosphorylation and stabilization are unknown.

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