Figure 2: RAN translation in repeat expansion disorders.

Repeat associated non-AUG translation at three repeat expansions are laid out schematically. Experimentally determined initiation sites are listed for individual reading frames where determined, although in all cases initiation may also occur within the repeat itself. A) A G₄C₂ hexanucleotide repeat in the first intron of C9Orf72 is bidirectionally transcribed. Whether the repeat is translated as a spliced intron or as part of a retained intron or other aberrant transcript is not known. A CUG located just 5’ to the repeat is utilized for initiation of poly(GA). It may also be utilized for poly(GR) translation with subsequent frameshifting. AUG codons reside upstream of poly(PR) and poly(PG) in the most common antisense transcripts. B) A CGG repeat in the 5’ leader/ 5’ UTR of FMR1 is also bidirectionally transcribed. An AUG in the poly(P) reading frame of ASFMR1 is utilized for initiation in this reading frame but it can also undergo RAN translation in this reading frame. FMRpolyR expression is nearly undetectable from reporter constructs. C) The CAG repeat in Huntington’s disease is located in the coding region of the HTT transcript and is also bidirectionally transcribed. ?: initiation site unknown, ‡: initiation in this frame exhibits cap-dependency.