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Cloettapreis_2004_Nr_32

mRNA into protein. A simplified description of the mechanism, which leads to TPO overproduction in family members that carry the mutation is shown in Figure 3. Figure 3: Mechanism of increased TPO protein production in family members carrying a TPO mutation. Physiologically, the translation of TPO mRNA is strongly inhibited by the presence of an upstream translational start codon (uAUG) located in the 5’-untranslated region (5’-UTR) of the TPO mRNA (Ghilardi et al., 1998). The ribosome (40S and 60S subunits) initiates synthesis of a short peptide and dissociated from the mRNA after encountering a stop codon. Therefore, under normal circumstances, production of TPO protein is very inefficient. In affected family members, exon-skipping removes the uAUG and allows efficient translation (Wiestner et al., 1998). Thus, more TPO protein is syn- thesized from the same amount of mRNA, leading to increase TPO serum levels. Directed mutagenesis of the uAUG in the TPO mRNA restored full translational efficiency, demonstrating that translational inhibition of TPO biosynthesis is entirely mediated by uORF (Ghilardi et al., 1998). To date, 3 additional mutations in the TPO gene have been described (Ghilardi et al., 1999; Jorgensen et al., 1998; Kondo et al., 1998). In all cases reported, the inheritance is autosomal dominant and the pheno- type is already manifest in childhood or at birth. The clinical findings in these families consist of a high platelet count, markedly elevated 46

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