Gene expression regulation by upstream open reading frames and human disease

PLoS Genet. 2013;9(8):e1003529. doi: 10.1371/journal.pgen.1003529. Epub 2013 Aug 8.


Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 5' Untranslated Regions / genetics
  • Disease / genetics*
  • Gene Expression Regulation*
  • Genetic Association Studies
  • Humans
  • Mutation
  • Open Reading Frames / genetics*
  • Protein Biosynthesis / genetics
  • RNA Stability*
  • Regulatory Sequences, Nucleic Acid / genetics


  • 5' Untranslated Regions

Grants and funding

Cristina Barbosa and Isabel Peixeiro were supported by Fellowships from Fundação para a Ciência e a Tecnologia (SFRH/BD/63581/2009 to CB and SFRH/BD/35962/2007 to IP). The funders had no role in the preparation of the manuscript.