In higher eukaryotes, the expression of about 1 gene in 10 is strongly regulated at the level of
messenger RNA (mRNA) translation into
protein. Negative regulatory effects are often mediated by the 5'-untranslated region (5'-UTR) and rely on the fact that the 40S ribosomal subunit first binds to the cap structure at the 5'-end of
mRNA and then scans for the first AUG
codon. Self-complementary sequences can form stable stem-loop structures that interfere with the assembly of the preinitiation complex and/or ribosomal scanning. These stem loops can be further stabilized by the interaction with
RNA-binding proteins, as in the case of
ferritin. The presence of AUG
codons located upstream of the physiological start site can inhibit translation by causing premature initiation and thereby preventing the ribosome from reaching the physiological
start codon, as in the case of
thrombopoietin (TPO). Recently, mutations that cause disease through increased or decreased efficiency of mRNA translation have been discovered, defining translational pathophysiology as a novel mechanism of human disease.
Hereditary hyperferritinemia/cataract syndrome arises from various point mutations or deletions within a protein-binding sequence in the 5'-UTR of the
L-ferritin mRNA. Each unique mutation confers a characteristic degree of
hyperferritinemia and severity of
cataract in affected individuals. Hereditary
thrombocythemia (sometimes called familial
essential thrombocythemia or familial
thrombocytosis) can be caused by mutations in upstream AUG
codons in the 5'-UTR of the TPO
mRNA that normally function as translational repressors. Their inactivation leads to excessive production of TPO and elevated platelet counts. Finally, predisposition to
melanoma may originate from mutations that create translational repressors in the 5'-UTR of the
cyclin-dependent kinase inhibitor-2A gene.