Hereditary thrombocythaemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene

Hereditary thrombocythaemia (HT) with clinical features very similar to ess ential thrombocythaemia (ET) has been found to be transmitted as an autosom al dominant trait in several families. Here we studied the pathogenesis of HT in a previously described Japanese kindred, We found markedly elevated t hrombopoietin (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 af fected family members. This mutation is located in the 5'-untranslated regi on (5'-UTR) of the TPO mRNA and when assayed in reticulocyte lysates, impro ved translational efficiency of in vitro transcribed TPO mRNA, Cell lines t ransfected 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 o f how the mutation partially disables the physiologic repression of TPO tra nslation and thereby causes thrombocytosis. This is the third family in whi ch HT has been caused by the loss of translational inhibition of TPO mRNA.