Translational pathophysiology: a novel molecular mechanism of human disease

In higher eukaryotes, the expression of about 1 gene in 10 is strongly regu lated at the level of messenger RNA (mRNA) translation into protein. Negati ve 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 in terfere with the assembly of the preinitiation complex and/or ribosomal sca nning. These stem loops can be further stabilized by the interaction with R NA-binding proteins, as in the case of ferritin, The presence of AUG codons located upstream of the physiological start site can inhibit translation b y causing premature initiation and thereby preventing the ribosome from rea ching the physiological start codon, as in the case of thrombopoietin (TPO) , Recently, mutations that cause disease through Increased or decreased eff iciency of mRNA translation have been discovered, defining translational pa thophysiology as a novel mechanism of human disease. Hereditary hyperferrit inemia/cataract syndrome arises from various point mutations or deletions w ithin a protein-binding sequence in the 5'-UTR of the L-ferritin mRNA, Each unique mutation confers a characteristic degree of hyperferritinemia and s everity of cataract in affected individuals, Hereditary thrombocythemia (so metimes called familial essential thrombocythemia or familial thrombocytosi s) can be caused by mutations in upstream AUG codons in the 5'-UTR of the T PO mRNA that normally function as translational repressors, Their inactivat ion leads to excessive production of TPO and elevated platelet counts, Fina lly, predisposition to melanoma may originate from mutations that create tr anslational repressors in the 5'-UTR of the cyclin-dependent kinase inhibit or-2A gene. (Blood. 2000;95:3280-3288) (C) 2000 by The American Society of Hematology.