CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs

Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The diseasecausing repeats are translated in multiple reading frames and without an identifiable initiation codon. The molecular mechanism of this repeat -associated non-AUG (RAN) translation is not known. We find that expanded CAG repeats create new splice acceptor sites. Splicing of proximal donors to the repeats produces unexpected repeat -containing transcripts. Upon splicing, depending on the sequences surrounding the donor, CAG repeats may become embedded in AUG-initiated open reading frames. Canonical AUG-initiated translation of these aberrant RNAs may account for proteins that have been attributed to RAN translation. Disruption of the relevant splice donors or the in -frame AUG initiation codons is sufficient to abrogate RAN translation. Our findings provide a molecular explanation for the abnormal translation products observed in CAG trinucleotide repeat expansion disorders and add to the repertoire of mechanisms by which repeat expansion mutations disrupt cellular functions.