The ORF is defined as the part of a reading frame that has the potential to be translated; it consists of a sequence of nucleotide triplets that specify an amino acid chain. While the mRNA of a gene will have a principal ORF that specifies the main polypeptide product, there may be several other ORFs, each of which modulate the overall expression of the main protein product. The ORFs located upstream to the canonical initiation codon and out-of-frame with respect to the main coding sequence are called upstream (u)ORFs and are characterized by their own upstream starting codon (uAUG) and stop codon. At least half of the human transcripts contain uORFs. They correlate significantly with reduction of protein expression (30–80%) of the downstream ORF, with only a modest impact on mRNA levels.27 The uORF-mediated translational control can occur through different mechanisms, depending on the efficiency of uAUG ribosome recognition and of uORF translational termination.28 The uORFs can be generated or disrupted by genetic variants leading to dysregulation of gene expression and increased disease risk.27,29
