Familial essential thrombocythemia associated with one-base deletion in the 5'-untranslated region of the thrombopoietin gene.
Familial essential thrombocythemia (ET) is inherited in an autosomal-dominant manner. This finding implies that familial ET may arise as a consequence of a mutation(s) that activates platelet production. In 1994, the thrombopoietin (TPO) gene was isolated and cloned. The TPO-TPO receptor, encoded for by the c-mpl gene, are essential regulators of thrombopoiesis. Alterations of TPO or c-Mpl thus may constitute a pathogenic event leading to familial ET. In a case of familial ET presented in our institute, serum TPO levels were significantly elevated in affected members of the family as compared with nonaffected members. Moreover, we identified a one-base deletion in the 5'-untranslated region of the TPO gene in affected but not in nonaffected family members. In vitro experiments showed that the identified mutation increased TPO production. Based on our findings, we propose that this region of the TPO gene may play a crucial role in regulating TPO expression. Our results strongly suggest that the identified mutation leads to familial ET.
Third Department of Internal Medicine and the Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan. t-kondoh@med.hokudai.ac.jp
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Kondo
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Okabe
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Sanada
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Kurosawa
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Suzuki
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Kobayashi
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Hosokawa
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Asaka
D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000502:physiology; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D017384:Sequence Deletion; D013920:Thrombocythemia, Essential / Q000097:blood / Q000235:genetics*; D013926:Thrombopoietin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D014162:Transfection
D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin