An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia

Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained proliferation of megakaryocytes, which results in elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes and occasional leukaemic transformation1. The cause of ET is unknown. Hereditary thrombocythaemia (HT) with autosomal–dominant transmission has been described with manifestations similar to those of sporadic ET2–8. As the thrombopoietin gene (THRO) encodes a lineage–restricted growth factor with profound stimulatory effects on megakaryopoiesis and platelet production9,10, we tested the hypothesis that HT results from a mutation in the human THRO gene. In a Dutch family with eleven affected individuals7, the thrombopoietin protein (TPO) concentrations in serum were consistently elevated in individuals with HT. We derived an intragenic CA marker for the human THRO gene and performed linkage analysis in fourteen informative meioses in this family. This resulted in a lod score of 3.5 at θ=0. A G→C transversion was found in the splice donor site of intron 3 of the THRO gene in all affected family members. This mutation leads to THRO mRNAs with shortened 5′–untranslated regions (UTR) that are more efficiently translated than the normal THPO transcripts. We conclude that a splice donor mutation in THPO leads to systemic overproduction of TPO and causes thrombocythaemia.