title: Translational effects and coding potential of an upstream open reading frame associated with DOPA Responsive Dystonia.
abstract: Upstream open reading frames (uORFs) have emerged as major post-transcriptional regulatory elements in eukaryotic species. In general, uORFs are initiated by a translation start codon within the 5' untranslated region of a gene (upstream ATG; uATG), and they are negatively correlated with translational efficiency. In addition to their translational regulatory role, some uORFs can code for biologically active short peptides. The importance of uATGs/uORFs is further underscored by human diseases associated with single nucleotide polymorphisms (SNPs), which disrupt existing uORFs or introduce novel uORFs. Although several functional proteins translated from naturally occurring uORFs have been described, the coding potential of uORFs created by SNPs has been ignored because of the a priori assumption that these proteins are short-lived with no likely impact on protein homeostasis. Thus, studies on SNP-created uORFs are limited to their translational effects, leaving unexplored the potential cellular consequences of a SNP/uORF-encoded protein. Here, we investigate functionality of a uATG/uORF introduced by a +142C>T SNP within the GCH1 gene and associated with a familial form of DOPA Responsive Dystonia. We report that the +142C>T SNP represses GCH1 translation, and introduces a short, frame shifted uORF that encodes a 73-amino acid peptide. This peptide is localized within the nucleus and compromises cell viability upon proteasome inhibition. Our work extends the list of uATG/uORF associated diseases and advances research on peptides translated from SNP-introduced uORFs, a neglected component of the proteome.
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Lataisia
authors.initials: L
authors.lastname: Jones
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Lacy
authors.initials: L
authors.lastname: Goode
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Davila
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Brown
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: McCarthy
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Nutan
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA. Electronic address: Pradeep.bhide@med.fsu.edu.
authors.forename: Pradeep G
authors.initials: PG
authors.lastname: Bhide
authors.affiliation: Center for Brain Repair and Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, USA. Electronic address: ionarm999@gmail.com.
authors.forename: Ioanna A
authors.initials: IA
authors.lastname: Armata
mesh_terms: D045744:Cell Line, Tumor; D003062:Codon; D020821:Dystonic Disorders / Q000151:congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis
chemical_list: D003062:Codon; D006136:GTP Cyclohydrolase
keywords: 5′Untranslated region; Coding potential; DOPA Responsive Dystonia; DYT5; Gene expression; Regulation of translation; Short peptides; Upstream open reading frames