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Hereditary thrombocythaemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene
Author(s) -
Ghilardi Nico,
Wiestner Adrian,
Kikuchi Masahiro,
Ohsaka Akimichi,
Skoda Radek C.
Publication year - 1999
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1999.01710.x
Subject(s) - thrombopoietin , microbiology and biotechnology , biology , point mutation , messenger rna , untranslated region , mutation , complementary dna , transfection , gene , mutant , thrombocytosis , genetics , platelet , immunology , haematopoiesis , stem cell
Hereditary thrombocythaemia (HT) with clinical features very similar to essential thrombocythaemia (ET) has been found to be transmitted as an autosomal dominant trait in several families. Here we studied the pathogenesis of HT in a previously described Japanese kindred. We found markedly elevated thrombopoietin (TPO) serum levels in all affected individuals and identified a novel point mutation in the TPO gene, a G → T transversion at position 516 of the TPO mRNA (G516T) that co‐segregated with the HT phenotype in all affected family members. This mutation is located in the 5′‐untranslated region (5′‐UTR) of the TPO mRNA and when assayed in reticulocyte lysates, improved translational efficiency of in vitro transcribed TPO mRNA. Cell lines transfected with the mutant TPO cDNA secreted up to 8‐fold more TPO protein than cells transfected with the normal cDNA. We provide a molecular model of how the mutation partially disables the physiologic repression of TPO translation and thereby causes thrombocytosis. This is the third family in which HT has been caused by the loss of translational inhibition of TPO mRNA.