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. 2018 Jul;97(3):665-677.

Models and Mechanisms of Repeat Expansion Disorders: A Worm's Eye View

Free PMC article

Models and Mechanisms of Repeat Expansion Disorders: A Worm's Eye View

Paige Rudich et al. J Genet. .
Free PMC article


The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system Caenorhabditis elegans has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.


Figure 1.
Figure 1.. Newly discovered HD RAN peptides may contribute to the pathogenesis of Huntington’s disease and other CAG repeat repeat expansion disorders.
PolyQ proteins in C. elegans and other models exert toxicity through multiple cellular pathways including disruptions in protein quality control, autophagy, and mitochondrial function. RAN translation of the CAG repeat gives rise to four additional peptides which could contribute to HD neurodegeneration, either by enhancing polyQ toxicity, inhibiting known polyQ targets, or acting via novel polyQ-independent pathways.

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