Non-ATG-initiated translation directed by microsatellite expansions.

Department of Genetics Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

Proceedings of the National Academy of Sciences of the United States of America 2011 Jan 4

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Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.

Citation

Tao Zu, Brian Gibbens, Noelle S Doty, Mário Gomes-Pereira, Aline Huguet, Matthew D Stone, Jamie Margolis, Mark Peterson, Todd W Markowski, Melissa A C Ingram, Zhenhong Nan, Colleen Forster, Walter C Low, Benedikt Schoser, Nikunj V Somia, H Brent Clark, Stephen Schmechel, Peter B Bitterman, Geneviève Gourdon, Maurice S Swanson, Melinda Moseley, Laura P W Ranum. Non-ATG-initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences of the United States of America. 2011 Jan 4;108(1):260-5