title: Non-ATG-initiated translation directed by microsatellite expansions.
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.
authors.affiliation: Department of Genetics Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zu
authors.forename: Brian
authors.initials: B
authors.lastname: Gibbens
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Doty
authors.forename: Mário
authors.initials: M
authors.lastname: Gomes-Pereira
authors.forename: Aline
authors.initials: A
authors.lastname: Huguet
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Stone
authors.forename: Jamie
authors.initials: J
authors.lastname: Margolis
authors.forename: Mark
authors.initials: M
authors.lastname: Peterson
authors.forename: Todd W
authors.initials: TW
authors.lastname: Markowski
authors.forename: Melissa A C
authors.initials: MA
authors.lastname: Ingram
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Nan
authors.forename: Colleen
authors.initials: C
authors.lastname: Forster
authors.forename: Walter C
authors.initials: WC
authors.lastname: Low
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.forename: Nikunj V
authors.initials: NV
authors.lastname: Somia
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmechel
authors.forename: Peter B
authors.initials: PB
authors.lastname: Bitterman
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gourdon
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.forename: Melinda
authors.initials: M
authors.lastname: Moseley
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
mesh_terms: D000595:Amino Acid Sequence; D015152:Blotting, Northern; D002460:Cell Line; D003001:Cloning, Molecular; D018387:Codon, Initiator / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016086:Lentivirus; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009223:Myotonic Dystrophy / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D018387:Codon, Initiator; D017931:DNA Primers; D010455:Peptides; C019529:polyalanine; C027794:polyserine; C097188:polyglutamine