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Non-ATG-initiated translation directed by microsatellite expansions.

Authors
  • Zu, Tao1
  • Gibbens, Brian
  • Doty, Noelle S
  • Gomes-Pereira, Mário
  • Huguet, Aline
  • Stone, Matthew D
  • Margolis, Jamie
  • Peterson, Mark
  • Markowski, Todd W
  • Ingram, Melissa A C
  • Nan, Zhenhong
  • Forster, Colleen
  • Low, Walter C
  • Schoser, Benedikt
  • Somia, Nikunj V
  • Clark, H Brent
  • Schmechel, Stephen
  • Bitterman, Peter B
  • Gourdon, Geneviève
  • Swanson, Maurice S
  • And 2 more
  • 1 Department of Genetics Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Jan 04, 2011
Volume
108
Issue
1
Pages
260–265
Identifiers
DOI: 10.1073/pnas.1013343108
PMID: 21173221
Source
Medline
Language
English
License
Unknown

Abstract

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.

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