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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3280-3288
REVIEW ARTICLE
Translational pathophysiology: a novel molecular mechanism of
human disease
Mario Cazzola and
Radek C. Skoda
From the Department of Hematology, University of Pavia Medical
School and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Policlinico S. Matteo, Pavia, Italy; and Clinical Cooperation Unit for
Molecular Hematology-Oncology, German Cancer Research Center (DKFZ),
and Department of Medicine V, University of Heidelberg, Heidelberg,
Germany.
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.
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