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. 2021 Jun 1;15:660693. doi: 10.3389/fncel.2021.660693

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Copyright © 2021 Nishimura and Arias.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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C9orf72 and other repeat expansion disease mechanisms. Nucleotide repeat expansions located at intron or untranslated regions (UTRs) cause three main disease-related features, haploinsufficiency in C9orf72 (A), myotonic Dystrophy type 1 (DM1; D), myotonic dystrophy type 2 (G), and Friedreich’s ataxia (FRDA) (J). mRNAs containing repeat expansions form G-quadruplex (C9orf72) and RNA hairpin structures (myotonic dystrophy type 1 and 2). These RNA hairpins will accumulate and form RNA foci (B,E,H), which will sequester RNA binding proteins (RBPs) including hnRNP-H in C9orf72 and Muscleblind like Splicing Regulator 1 (MBNL1) in myotonic dystrophy type 1 and 2. Repeat-associated non-AUG (RAN) translation produces peptides from the sense and antisense strands in C9orf72 (C), myotonic dystrophy type 1 (F), and myotonic dystrophy type 2 (I). The exception lies in FRDA disease mechanisms. In this disease, the repeat expansion causes DNA hypermethylation and gene expression dysregulation of neighboring genes (K). The mRNA forms hairpins, which are degraded by Dicer (L), leading to downregulation of frataxin (M). In this disease, RNA foci and RAN translation were not observed.